[go: up one dir, main page]

WO2025212960A1 - Antimicrobials and discovery thereof - Google Patents

Antimicrobials and discovery thereof

Info

Publication number
WO2025212960A1
WO2025212960A1 PCT/US2025/023053 US2025023053W WO2025212960A1 WO 2025212960 A1 WO2025212960 A1 WO 2025212960A1 US 2025023053 W US2025023053 W US 2025023053W WO 2025212960 A1 WO2025212960 A1 WO 2025212960A1
Authority
WO
WIPO (PCT)
Prior art keywords
compounds
substructure
independently selected
docket
pct
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/023053
Other languages
French (fr)
Inventor
James Joseph COLLINS
Aarti KRISHNAN
Jacqueline Alexus VALERI
Felix J. WONG
Wengong JIN
Melis Nuray Anahtar
Andreas LUTTENS
Bruce Blough
Chunyang JIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Center For Drug Discovery Rti International
General Hospital Corp
Massachusetts Institute of Technology
Broad Institute Inc
Harvard University
Original Assignee
Center For Drug Discovery Rti International
General Hospital Corp
Massachusetts Institute of Technology
Broad Institute Inc
Harvard University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Center For Drug Discovery Rti International, General Hospital Corp, Massachusetts Institute of Technology, Broad Institute Inc, Harvard University filed Critical Center For Drug Discovery Rti International
Publication of WO2025212960A1 publication Critical patent/WO2025212960A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
    • G06N3/00—Computing arrangements based on biological models

Definitions

  • bacterial pathogens such as Staphylococcus aureus and Neisseria gonorrhoeae have been identified as high priority targets by the U.S. Centers for Disease Control and Prevention (the “CDC”) due to widespread incidence of antimicrobial resistance.
  • the CDC U.S. Centers for Disease Control and Prevention
  • difficulties in identifying and developing antimicrobial compounds tend to hinder the development of such compounds.
  • the cost of developing antimicrobial compounds is quite high.
  • traditional techniques for identifying and/or developing antimicrobial compounds are often quite slow. As such, there is a significant need for the identification and development of FIG.1 1 Docket No.: BI-11213-PCT antimicrobial compounds.
  • compositions for treating or preventing a microbial infection in a subject include a compound of structure VI as defined herein.
  • the compositions include a compound of structure VII as defined herein.
  • compositions include a compound of substructure I bonded to Z1 and substructure Z2 as follows: R1A H wherein: FIG.1 2 Docket No.: BI-11213-PCT R 1 – R 4 are independently selected from C or N with at least two, more typically at least three, and quite possibly all four of R 1 - R 4 being C; R 5 – R 9 are independently selected from C or N with at least three, more typically at least four, and quite possibly all five of R 5 - R 9 being C; R 1A – R 4A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, OH or halogen, with R 1A – R 4A only being nothing where, respectively, R 1 – R 4 is selected as N; and R 5A – R 9A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, OH,
  • compositions include the compound according to substructure I according to descriptions herein, and Z1 and substructure Z2 according to descriptions herein, wherein: R 1 – R 4 are C; R 5 – R 7 are C, and R 8 – R 9 are independently selected from C or N, with only one of R 8 or R 9 being N, if any; R 10 is S or O but is typically O.
  • the screening of the library of initial substructures includes removing initial substructures of the library of initial substructures wherein the initial substructures exhibit one or more of: 1) predicted cytotoxicity above a threshold; 2) PAINS or Brenk substructures; or 3) structural similarity to compounds that exhibit activity against the target microbe.
  • the at least one active chemical substructure is provided to the generative module and the generative module includes an algorithm that provides a computational framework that starts with at least one active chemical substructure and generates the candidate compounds by adding, replacing, or deleting atoms and functional groups.
  • FIG. 25B depicts a graph of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIG. 25C depicts a graph of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIGs. 26A and 26B depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIGs. 26C and 26D depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIGs. 26E depicts a graph of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIGs. 25C depicts a graph of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIG. 26A and 26B depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIGs. 26C and 26D depict graphs of data useful for aspects of discovery of chemical compounds (e
  • FIGs. 27A and 27B depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIGs. 27C and 27D depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIG. 27E depicts graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIGs. 28A and 28B depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIGs. 28C and 28D depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIG. 30A depicts examples of chemical compounds (e.g., antimicrobial compounds) generated according to aspects of the present disclosure.
  • FIG. 30B depicts a graph of exemplary data resulting from testing of the chemical compounds of FIG.30A in accordance with aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIG. 30C depicts a graph of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIG. 30D and 30E depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIG. 31A depicts examples of chemical compounds (e.g., antimicrobial compounds) discovered (e.g., designed) according to aspects of the present disclosure.
  • FIG. 31A depicts examples of chemical compounds (e.g., antimicrobial compounds) discovered (e.g., designed) according to aspects of the present disclosure.
  • FIG. 31B depicts a table of data and chemical variations related to chemical compounds (e.g., antimicrobial compounds) generated according to aspects of the present disclosure.
  • FIG. 31C depicts examples of chemical compounds (e.g., antimicrobial compounds) generated according to aspects of the present disclosure.
  • FIG.1 16 Docket No.: BI-11213-PCT depicts a graph of exemplary data resulting from testing of the chemical compounds of FIG. 31B and 31C and other compounds in accordance with aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIG. 32 is an illustration of an example environment that is operable to implement aspects of discovery of chemical compounds (e.g., antimicrobial compounds).
  • FIG.33A depicts a table of compounds and respective data for those compounds in accordance with aspects of the present disclosure.
  • FIG.33B depicts a table of compounds and respective data for those compounds in accordance with aspects of the present disclosure.
  • FIG.33C depicts a table of compounds and respective data for those compounds in accordance with aspects of the present disclosure.
  • FIG.34 depicts a table of data for compounds in accordance with aspects of the present disclosure.
  • FIG.35 depicts graphs of exemplary data resulting from testing of the chemical compounds in accordance with aspects of discovery of the present disclosure.
  • FIG.36 depicts a table of data for compounds in accordance with aspects of the present disclosure.
  • FIG.37 depicts graphs of exemplary data resulting from testing of the chemical compounds in accordance with aspects of discovery of the present disclosure.
  • FIG.38 depicts a graph of exemplary data resulting from testing of the chemical compounds in accordance with aspects of discovery of the present disclosure.
  • the current disclosure relates, at least in part, to the discovery (e.g., identification, development and/or generation) of antimicrobial compounds.
  • the current disclosure relates to antimicrobial compounds and substructures of antimicrobial compounds discovered (e.g., identified and/or generated) using in silico methods that employ machine learning to achieve robust and accurate predictive identification of effective antimicrobial compounds and/or substructures.
  • Substructures and compounds can be so identified from compound and/or substructure (also referred to herein as fragments) databases or from generation of compounds and/or antimicrobial compounds or both.
  • the current disclosure also relates, at least in part to the discovery (e.g., identification and/or generation) of substructures that form a part of the antimicrobial compounds. Development of antimicrobial compounds that include and/or are based on the substructures show that the substructures, in certain circumstances, define new classes of antimicrobial compounds.
  • Substructure I One substructure developed and/or identified in accordance with the present disclosure is substructure I shown below: FIG.1 18 Docket No.: BI-11213-PCT R1A H [0084] Compounds having substructure I have been found to have particularly desirable activity against Staphylococcus aureus but are not so limited unless specifically stated.
  • Substructure I allows for multiple variations in an embodiment I as follows: R 1 – R 4 are independently selected from C or N with at least two, more typically at least three, and quite possibly all four of R 1 - R 4 being C; R 5 – R 9 are independently selected from C or N with at least three, more typically at least four, and quite possibly all five of R 5 - R 9 being C; R 1A – R 4A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, OH or halogen, with R 1A – R 4A only being nothing where, respectively, R 1 – R 4 is selected as N; and FIG.1 19 Docket No.: BI-11213-PCT R 5A – R 9A are independently selected from nothing, H, CH3, substituted or unsubstituted C 2 – C 4 alkyl or alkylene, OH, or halogen, with R 5A – R 9A only being nothing if, respectively
  • Substructure I further allows for multiple variations in an embodiment II as follows: R 1 – R 4 are C; R 5 – R 7 are C, and R 8 – R 9 are independently selected from C or N, with only one of R 8 or R 9 being N, if any; R 1A – R 4A are independently selected from H or halogen, with only one, if any, of R 1A – R 4A being halogen, and the halogen is selected from F, Br, and Cl; and R 5A – R 7A are independently selected from H or halogen, with only one, if any, of R 5A – R 7A being halogen, and the halogen is selected from F, Br, and Cl; R 8A – R 9A are independently selected from nothing, H or halogen, with only one, if any, of R 8A – R 9A being halogen and the halogen being selected from F, Br and Cl, and with R 8A or R 9A being nothing if, respectively, R 8 or R 9
  • Substructure I also allows for multiple variations in an embodiment III as follows: R 1 – R 4 are C; R 5 – R 9 are C; R 1A , R 2A , and R 4A are H, and R 3A is H or halogen, the halogen being selected from F and Cl; R 5A , R 6A , R 8A and R 9A are H; and FIG.1 20 Docket No.: BI-11213-PCT R 7A is H or halogen, the halogen being selected from F, Br, and Cl or, more particularly, from F and Cl.
  • any of the embodiments I, II and III can be, as appropriate, further defined by at least one, two, three, or any possible combination of the following: 1) at least two of R 1A – R 4A are H; 2) at least three of R 1A – R 4A are H; 3) at least one of R 1A – R 4A is halogen; 4) at least two of R 1A – R 4A are halogen; 5) at least two of R 5A – R 9A are H; 6) at least three of R 5A – R 9A are H; 7) at least one of R 5A – R 9A is halogen; 8) at least two of R 5A – R 9A are halogen; and/or 9) at least three of R 5A – R 9A are halogen.
  • halogen of the substructure I can be Cl, Fl, Br, or any combination thereof unless otherwise indicated.
  • substructure I includes all stereoisomers thereof.
  • Substructure II Another substructure developed and/or identified in accordance with the present disclosure is substructure II shown below: FIG.1 21 Docket No.: BI-11213-PCT Substructure II O [0093] activity against Neisseria gonorrhoeae but are not so limited unless specifically stated.
  • Substructure II allows for multiple variations in an embodiment I as follows: R 1 – R 5 are independently selected from C or N with at least three, more typically at least four, and quite possibly all five of R 1 -R 5 being C; and R 1A – R 5A are independently selected from nothing, H, CH 3 , substituted or unsubstituted C 2 – C 4 alkyl or alkylene, OH or halogen, with R 1A – R 5A only being nothing if, respectively, R 1 – R 5 is selected as N.
  • substructure II In defining substructure II, at least one, two, three, or any possible combination of the following: 1) at least two of R 1A – R 5A are H; 2) at least three of R 1A – R 5A are H; 3) at least one of R 1A – R 5A is halogen; and/or 4) at least two of R 1A – R 5A are halogen. [0096] For each selection of halogen of the substructure II, the halogen can be Cl, F, Br, or any combination thereof unless otherwise indicated. [0097] It is understood that substructure II includes all stereoisomers thereof.
  • FIG.1 22 Docket No.: BI-11213-PCT [0098] Antimicrobial Compounds [0099] Antimicrobial compounds of the present disclosure include compounds that include substructure I and substructure II as well as additional compounds. [0100] Compounds with Substructure I [0101] Antimicrobial compounds that include substructure I will typically include compounds that have Z1 and substructure Z2 bonded to substructure I as shown below: [0102] R1A H However, it is contemplated that Z1 and/or substructure Z2 could be bonded to substructure I at different locations.
  • substructure Z2 is substructure Z2 1 as follows: FIG.1 23 Docket No.: BI-11213-PCT R 11A R 12A
  • Z1 is H or CH3, typically H
  • substructure Z2 is substructure Z2 1 , which allows for variation as follows:
  • R 10 is selected from CH2, NH, S or O, but is typically either S or O;
  • R 11 – R 15 are independently selected from C or N, with no more than two of R 11 – R 15 being N, and more typically no more than one of R 11 – R 15 being N;
  • R 11A – R 15A are independently selected from nothing, H, CH 3 , substituted or unsubstituted C 2 – C 4 alkyl or alkylene, carboxyl, OH or halogen, with R 11A – R 15A only being nothing if, respectively, R 11 – R 15 is selected as N; at least one of R 11A – R 15A is carboxyl;
  • R 10 is selected from S or O; R 11 – R 15 are independently selected from C or N, with no more than one of R 11 – R 15 being N;
  • FIG.1 24 Docket No.: BI-11213-PCT R 11A – R 15A are independently selected from nothing, H, CH3, and carboxyl with R 11A – R 15A only being nothing if, respectively, R 11 – R 15 is selected as N; one of R 11A – R 15A is carboxyl; and at least three of R 11A – R 15A are H.
  • Z1 is H and substructure Z2 is substructure Z2 1 , which allows for variation as follows: R 10 is O; R 11 – R 15 are C; R 11A – R 15A are independently selected from H and carboxyl; one of R 11A – R 15A is carboxyl; and four of R 11A – R 15A are H.
  • R 10 is O
  • R 11 – R 15 are C
  • R 11A – R 15A are independently selected from H and carboxyl
  • one of R 11A – R 15A is carboxyl
  • four of R 11A – R 15A are H.
  • the present disclosure specifically contemplates compounds as follows: embodiment I of substructure I with embodiment A of Z1 and substructure Z2; embodiment I of substructure I with embodiment B of Z1 and substructure Z2; embodiment I of substructure I with embodiment C of Z1 and substructure Z2; embodiment II of substructure I with embodiment A of Z1 and substructure Z2; embodiment II of substructure I with embodiment B of Z1 and substructure Z2; embodiment II of substructure I with embodiment C of Z1 and substructure Z2; embodiment III of substructure I with embodiment A of Z1 and substructure Z2; embodiment III of substructure I with embodiment B of Z1 and substructure Z2; embodiment III of substructure I with embodiment C of Z1 and substructure Z2.
  • FIG.1 25 Docket No.: BI-11213-PCT
  • SA1 4-((5- acid [0110]
  • FIG.1 26 Docket No.: BI-11213-PCT
  • SA2 4-(((5-chl o)benzoic acid [0111]
  • SA3 4-[(2- - sulfanylbenzoic acid [0112]
  • FIG.1 27 Docket No.: BI-11213-PCT
  • SA4 4-[(6-bro yl]sulfanylbenzoic acid [0113]
  • SA5 4-((4- [0114] FIG.1 28 Docket No.: BI-11213-PCT
  • SA6 4-((6-c nzoic acid [0115]
  • SA7 3-((5- acid [0116]
  • SA8 2-((5-chlo oic acid [0117]
  • SA9 4-((5- acid [0118]
  • FIG.1 30 Docket No.: BI-11213-PCT
  • SA10 4-((4-chlo ic acid [0119]
  • SA11 4-((5- acid [0120]
  • FIG.1 31 Docket No.: BI-11213-PCT
  • Another antimicrobial compound of the present disclosure is compound III shown below: PCT N-(3,4-dichlorophenyl)-8-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-3- hydroxy-3,4,6,6a,8,9,10,10a-octahydro-2H-pyrano[2,3-c][1,5]oxazocine-1- carboxamide [0133] Compound III has been shown to exhibit significant activity against Staphylococcus aureus. With reference to at least FIGs.
  • Antimicrobial compounds of the present disclosure can also have structure IV shown below: R 1 and R 2 are independently selected from H, alkoxy (e.g., methoxy), halogen, or a combination thereof; when R 1 or R 2 is alkoxy (e.g., methoxy), the other of R 1 or R 2 is typically H, although not required unless specifically stated; FIG.1 39 Docket No.: BI-11213-PCT when R 1 or R 2 is halogen, the other of R 1 or R 2 is typically H, although not required unless specifically stated; and/or when R 1 or R 2 is halogen, the halogen is typically selected from F, Br, or Cl, and more typically is F.
  • R 1 and R 2 are independently selected from H, alkoxy (e.g., methoxy), halogen, or a combination thereof; when R 1 or R 2 is alkoxy (e.g., methoxy), the other of R 1 or R 2 is typically H, although not required unless specifically stated; FIG.1 39
  • Compounds of structure IV have been shown to exhibit significant activity against Staphylococcus aureus. With reference to at least FIGs.6H, and 6I, compounds of different variations and stereochemistries of structure IV have been shown to exhibit significant activity against Staphylococcus aureus as is discussed further herein. As such, compounds of structure IV and all various stereochemistries thereof are antimicrobial compounds of the present disclosure.
  • the compound[s] include at least one, two, three, or any possible combination of the following: 1) R 1 is halogen; 2) R 5 is halogen; 3) R 3 is trifluoromethyl; 4) three of R 1 , R 2 , R 3 , R 4 , and R 5 are H; and/or four of R 1 , R 2 , R 3 , R 4 , and R 5 are H. [0140] For each selection of halogen for structure V, the halogen is Cl, F, Br, and is typically Cl, unless otherwise indicated. [0141] Compounds of structure V has been shown to exhibit significant activity against Staphylococcus aureus. With reference to at least FIGs.
  • Antimicrobial compounds that include substructure II will typically include compounds that have substructure Y1 bonded to substructure II as shown below: Substructure II O Y1 [0145] However, it is contemplated that Y1 could be bonded to substructure II at different locations.
  • substructure Y1 is as follows: R 12 O R 10 FIG.1 11213-PCT [0147]
  • substructure Y1 allows for variation as follows: R 6 – R 10 are independently selected from H, CH 3 , and halogen, with no more than one of R 6 – R 10 being CH3, no more than three, and more typically no more than two of R 6 – R 10 being halogen, and at least two, and more typically at least three of R 6 – R 10 being H;
  • R 11 is selected from CH2, or C2-C4 alkyl or alkylene, and is typically C2H4; and
  • R 12 is selected from H, CH3, or C2-C4 alkyl or alkylene, and is typically CH3.
  • the compound includes any combination of the following: three of R 6 – R 10 are H; two of R 6 – R 10 are halogen; the halogen(s) of R 6 – R 10 are selected from F, Cl and Br; the halogen(s) of R 6 – R 10 are Cl; R 11 is C 2 H 4 ; and/or the halogen(s) of R 6 – R 10 , if any, are at R 8 and/or R 9 .
  • substructure Y1 is as follows: R 10 FIG.1 Docket No.: BI-11213-PCT [0150]
  • substructure Y1 allows for variation as follows: R 6 – R 10 are independently selected from H, CH3, and halogen, with no more than one of R 6 – R 10 being CH3, no more than three, and more typically no more than two of R 6 – R 10 being halogen, and at least two and more typically at least three of R 6 – R 10 being H;
  • R 11 is selected from CH2, or C2-C4 alkyl or alkylene and is typically CH2; and
  • R 12 is selected from H, CH 3 , or C 2 -C 4 alkyl or alkylene and is typically CH 3 .
  • the compounds includes any combination of the following: three of R 6 – R 10 are H; two of R 6 – R 10 are halogen; the halogen(s) of R 6 – R 10 are selected from F, Cl and Br; the halogen(s) of R 6 – R 10 are Cl; and/or R 11 is CH2, the halogen(s) of R 6 – R 10 , if any, are at R 7 and/or R 8 .
  • Y1 is as follows: [0153] FIG.1 44 Docket No.: BI-11213-PCT R 10 [0154] In embodiment C of compounds that include substructure II and substructure Y1, substructure Y1 allows for variation as follows: R 6 – R 9 are independently selected from C or N, with typically at least one, two or three of R 6 – R 9 being N and one or two of R 6 – R 9 being C; and R 10 is independently selected from H, CH3, or CH2CH3 and is bonded to one of R 6 – R 9 , which has been independently selected as N.
  • substructure Y1 can alternatively be selected from any combination of the following: , FIG.1 BI-11213-PCT and/or N .
  • the embodiments of substructure II can be matched or combined with any of the variations of the embodiments of substructure Y1.
  • Compounds that have been found to have activity against Neisseria gonorrhoeae and which may or may not have substructure II can also be selected from any combination of the following: FIG.1 46 Docket No.: BI-11213-PCT
  • FIG.1 48 Docket No.: BI-11213-PCT
  • NG3 (3S)-1-(3,4-dichlorophenyl)pyrrolidin-3-amine
  • NG4 (S)-N-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-1-methyl-1H-pyrazole-4- carboxamide
  • FIG.1 49 Docket No.: BI-11213-PCT
  • FIG.1 51 Docket No.: BI-11213-PCT
  • Antimicrobial compounds of the present disclosure can also have structure VI shown below: [0167] FIG.1 52 Docket No.: BI-11213-PCT
  • R 1 is independently selected from H, halogen (e.g., Cl), or C1-C2 alkyl (e.g., methyl);
  • R 2 is independently selected from H or halogen (e.g., Cl);
  • R 3 is independently selected from H or halogen (e.g., Cl or F);
  • R 4 is independently selected from H or C1-C2 alkyl (e.g., methyl);
  • R 5 is independently selected from H, or halogen (e.g., Cl);
  • R 6 is independently selected from H, alkoxy (e.g., methoxy) or halogen (e.g., Cl); and/or A- is an anion.
  • the compound[s] includes at least one, two, three, or any possible combination of the following: 1) R 1 is methyl or Cl; 2) R 2 is Cl; 3) R 3 is Cl or F; 4) R 4 is methyl; 5) R 5 is Cl; 6) R 6 is methoxy or Cl; 7) R 7 is methyl; 8) R 1 is H; 9) R 2 is H; 10) R 3 is H; 11) R 4 is H; 12) R 5 is H; 13) R 6 is H; and/or 14) R 7 is H.
  • the compounds may be compounds wherein R 1 is H, methyl or Cl, R 2 is Cl or H, R 3 is Cl, F or H and R 4 is H or methyl, wherein at least one of R 1 -R 4 is not H, optionally wherein one or two of R 1 -R 4 is not H.
  • the compounds may be compounds wherein R 5 is H or Cl and R 6 is Cl or methoxy, optionally wherein R 5 is H or Cl and R 6 is Cl or R 5 is H and R 6 is methoxy.
  • the compounds of structure VI are positively charged as indicated by the “+” sign.
  • the positive charge may be located at or adjacent either of the nitrogen atoms or may be mobile between the nitrogen atoms.
  • FIG.1 53 Docket No.: BI-11213-PCT indicated by the dashed and angled line extending between the nitrogen atoms adjacent the “+” sign.
  • the structure VI above may be alternatively drawn with the “+” sign located at or adjacent one of the two nitrogen atoms to indicate where the positive charge is believed to be located a substantial portion or majority of the time.
  • the positive charge can be countered or balanced by a negatively charged atom or atoms (anion[s]), which may for example be Fl-, Cl-, Br-, or OH- or another suitable anion, with the compound including the anion in solid or dissolved form.
  • NG10 3-( enyl)methyl]-6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-1-ium;chloride; [0175] [0176] NG11: 3- - methyl]-6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-1-ium;chloride; [0177] FIG.1 55 Docket No.: BI-11213-PCT
  • NG12 3- methyl]-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; [0179] [0180] NG13: 1-[ - -6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-1-ium;chloride; [0181] FIG.1 56 Docket No.: BI-11213-PCT
  • NG14 1-[( hlorophenyl)-6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-1-ium;chloride; [0183] [0184] NG15: - methyl]-6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-1-ium;chloride; and/or [0185] FIG.1 57 Docket No.: BI-11213-PCT
  • NG16 1 7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride.
  • the positive charge for compounds NG10 through NG16 is shown as located at or adjacent one of the two nitrogen atoms as a convention that indicates where the positive charge is believed to be located a substantial portion or majority of the time for a selected compound.
  • the actual location of the positive charge, at any given time can be at or adjacent the other nitrogen atom or mobile between the nitrogen atoms depending upon various conditions.
  • each of compounds NG10 through NG 16 and other compounds of structure VI could be similarly represented by replacing the core of the structure of the compound with the following: FIG.1 58 Docket No.: BI-11213-PCT , and the interpretation of the e the same but without an indication of where the positive charge is believed to be located a substantial portion or majority of the time.
  • the anion (A-) could be any one or a combination of the suitable anions disclosed herein.
  • Antimicrobial compounds of the present disclosure can also have structure VII shown below: [0189] Compounds of structure VII allow for variation as follows: R 1 is independently selected from H or halogen (e.g., Br); FIG.1 59 Docket No.: BI-11213-PCT R 2 is independently selected from H or C1-C2 alkyl (e.g., methyl); R 3 is independently selected from H or OH; R 4 is independently selected from H or OH; and/or R 5 is independently selected from H, OH or alkoxy (e.g., methoxy). [0190] In defining compounds of structure VII, typically at least one, more typically at least two and even possibly all three of R 3 -R 5 is/are OH.
  • the compound[s] include at least one, two, three, or any possible combination of the following: 1) R 1 is Br; 2) R 2 is methyl; 3) R 3 is OH; 4) R 4 is OH; 5) R 5 is OH; 6) R 5 is methoxy; 7) R 1 is H; 8) R 2 is H; 9) R 3 is H; 10) R 4 is H; and/or 11) R 5 is H.
  • the compounds may be compounds wherein R 1 is H or Br, R 2 is H or methyl, R 3 is OH, R 4 is H or OH and R 5 is OH or methoxy.
  • NG19 4-(4-p ,, l [0196]
  • NG20 4-[4-(2-bromophenoxy)-1H-pyrazol-5-yl]benzene-1,3-diol [0197]
  • NG21 5-me y y p y py yl)phenol
  • Additional antimicrobial compounds of the present disclosure having activity against Neisseria gonorrhoeae are as follows: [0199] NG22: - [0200] FIG.1 62 Docket No.: BI-11213-PCT
  • NG23 N , l-2-amine
  • Additional antimicrobial compounds of the present disclosure having activity against Neisseria gonorrhoeae are shown in the figures including at least FIGs.7A-7D, 8, 14, 17, 20, 30A, and 31C and are further described herein. [0203] It is understood that for each substructure, compound, chemical fragment and so on, all stereoisomers are included unless otherwise stated or stereochemistry is specifically indicated.
  • antimicrobial compounds of the present disclosure can be defined by their activity against (i.e., ability FIG.1 63 Docket No.: BI-11213-PCT to kill or inhibit growth) Staphylococcus aureus and/or Neisseria gonorrhoeae. Techniques for minimum inhibitory concentration (MIC) and bacterial growth are described in detail in the experimental methods section of the disclosure.
  • MIC minimum inhibitory concentration
  • Antimicrobial compounds active against Staphylococcus aureus particularly those having substructure I but others as well, exhibit an MIC according to the described techniques of less than 32 ⁇ g/mL, 16 ⁇ g/mL, 8 ⁇ g/mL, 2 ⁇ g/mL, or 1 ⁇ g/mL.
  • Antimicrobial compounds active against Neisseria gonorrhoeae particularly those having substructure II but others as well, exhibit an MIC according to the described techniques of less than 64 ⁇ g/mL, 32 ⁇ g/mL, 16 ⁇ g/mL, 8 ⁇ g/mL, 5 ⁇ g/m, 2 ⁇ g/mL, or 1 ⁇ g/mL.
  • Chlamydomonas is used as a model organism for molecular biology, especially studies of flagellar motility and chloroplast dynamics, biogeneses, and genetics. Chlamydomonas contain ion channels that are directly activated by light.
  • the Chlamydomonas genus includes, but is not limited to, the strain Chlamydomonas reinhardtii. Chlamydomonas reinhardtii is an especially well studied biological model organism, partly due to its ease of culturing and the ability to manipulate its genetics (e.g., Chlamydomonas reinhardtii CC-503 auto-fluorescent strain).
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • pharmaceutically acceptable ester refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound (e.g., an FDA-approved compound where administered to a human subject) or a salt thereof.
  • prodrugs refers to those prodrugs of certain compounds of the present application which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the FIG.1 76 Docket No.: BI-11213-PCT application.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of an agent of the instant disclosure, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V.
  • compositions intended for in vivo use are usually sterile.
  • compositions for parental administration are also sterile, substantially isotonic and made under GMP conditions.
  • Stabilization techniques include cross-linking, multimerizing, or linking to groups such as polyethylene glycol, polyacrylamide, neutral protein carriers, etc. in order to achieve an increase in molecular weight.
  • Other strategies for increasing retention include the entrapment of the agent, such as an antibiotic compound, in a biodegradable or bioerodible implant.
  • the rate of release FIG.1 77 Docket No.: BI-11213-PCT of the therapeutically active agent is controlled by the rate of transport through the polymeric matrix, and the biodegradation of the implant.
  • the transport of drug through the polymer barrier will also be affected by compound solubility, polymer hydrophilicity, extent of polymer cross-linking, expansion of the polymer upon water absorption so as to make the polymer barrier more permeable to the drug, geometry of the implant, and the like.
  • the implants are of dimensions commensurate with the size and shape of the region selected as the site of implantation.
  • Implants may be particles, sheets, patches, plaques, fibers, microcapsules and the like and may be of any size or shape compatible with the selected site of insertion.
  • the implants may be monolithic, i.e. having the active agent homogenously distributed through the polymeric matrix, or encapsulated, where a reservoir of active agent is encapsulated by the polymeric matrix.
  • the selection of the polymeric composition to be employed will vary with the site of administration, the desired period of treatment, patient tolerance, the nature of the disease/infection to be treated and the like. Characteristics of the polymers will include biodegradability at the site of implantation, compatibility with the agent of interest, ease of encapsulation, and a half- life in the physiological environment.
  • dosing frequency is three times per day, twice per day, once per day, once every other day, once weekly, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, or once monthly, once every two months, once every three months, or longer. Progress of the therapy is easily monitored by conventional techniques and assays.
  • the dosing regimen, including the antimicrobial compound administered, can vary over time independently of the dose used.
  • Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology.
  • Such preparatory methods include the steps of bringing the antimicrobial compound (also described herein as the active ingredient) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
  • FIG.1 81 Docket No.: BI-11213-PCT [0250]
  • Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.001% and 100% (w/w) and more typically between 0.1% and 50% (w/w) active ingredient.
  • compositions disclosed herein can be a part of the whole of an acceptable pharmaceutically acceptable carrier of the present disclosure. It is also contemplated that most any of the pharmaceutical excipients disclosed herein can be considered as separate from the pharmaceutically acceptable carrier of the present disclosure, but still part of the pharmaceutical compositions disclosed herein.
  • Pharmaceutically acceptable excipients/carriers used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils.
  • Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents/carriers include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents/carriers include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl- pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked poly(vinyl- pyrrolidone)
  • sodium carboxymethyl starch
  • Exemplary binding agents/carriers include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, FIG.1 84 Docket No.: BI-11213-PCT cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salt
  • preservatives/excipients/carriers include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, FIG.1 85 Docket No.: BI-11213-PCT imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • Other excipients/preservatives/carriers include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.
  • buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium FIG.1 86 Docket No.: BI-11213-PCT levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, monobasic sodium phosphate
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally FIG.1 88 Docket No.: BI-11213-PCT employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, FIG.1 89 Docket No.: BI-11213-PCT glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (
  • the dosage form may include a buffering agent.
  • Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • FIG.1 90 Docket No.: BI-11213-PCT [0276] The active ingredient (i.e., antimicrobial compound) can be in a micro- encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents.
  • Dosage forms for topical and/or transdermal administration of an active ingredient described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
  • transdermal patches which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be FIG.1 91 Docket No.: BI-11213-PCT controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin.
  • Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable.
  • Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions.
  • Topically administrable formulations may, for example, comprise from about 0.01% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles which comprise the active ingredient FIG.1 92 Docket No.: BI-11213-PCT and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers.
  • Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self- propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally, the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the FIG.1 93 Docket No.: BI-11213-PCT active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations FIG.1 94 Docket No.: BI-11213-PCT when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.
  • FIG.1 95 Docket No.: BI-11213-PCT decided by a physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the active agents and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous, intramuscular, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams, and/or drops
  • mucosal nasal
  • a drug e.g., an antimicrobial compound
  • a drug may be administered via a number of routes of administration, including but not limited to: subcutaneous, intravenous, intrathecal, intramuscular, intranasal, oral, transepidermal, parenteral, by inhalation, or intracerebroventricular.
  • injection or “injectable” as used herein refers to a bolus injection (administration of a discrete amount of an agent for raising its concentration in a bodily fluid), slow bolus injection over several minutes, or prolonged infusion, or several consecutive injections/infusions that are given at spaced apart intervals.
  • a formulation as herein defined is administered to the subject by bolus administration.
  • a drug e.g., an antimicrobial compound
  • other therapy of the instant disclosure is administered to the subject in an amount sufficient to achieve a desired effect at a desired site (e.g., reduction of bacterial infection, bacterial abundance, symptoms, etc.) determined by a skilled clinician to be effective.
  • a desired site e.g., reduction of bacterial infection, bacterial abundance, symptoms, etc.
  • the antimicrobial compound is administered at least once a year.
  • the antimicrobial compound is administered at least once a day.
  • the antimicrobial compound is administered at least once a week.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day.
  • the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell.
  • the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
  • a dose e.g., a single dose, or any dose of multiple doses described herein includes independently between 0.1 ⁇ g and 1 ⁇ g, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of an agent (e.g., an antibiotic) described herein.
  • an agent e.g., an antibiotic
  • a dose described herein includes independently between 1 mg and 3 mg, inclusive, of an agent (e.g., an antimicrobial compound) described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of an agent (e.g., an antimicrobial FIG.1 99 Docket No.: BI-11213-PCT compound) described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of an agent (e.g., an antimicrobial compound) described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of an agent (e.g., an antimicrobial compound) described herein.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a dose described herein is a dose to an adult human whose body weight is 70 kg.
  • an agent e.g., an antimicrobial compound
  • composition, as described herein can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents), which are different from the agent or composition and may be useful as, e.g., combination therapies.
  • the antimicrobial compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease or infection (e.g., an antibiotic tolerant or resistant bacterial infection) in a subject in need thereof, in preventing a disease or infection in a subject in need thereof, in reducing the risk of developing a disease or infection in a subject in need thereof, etc. in a subject or tissue.
  • activity e.g., activity (e.g., potency and/or efficacy) in treating a disease or infection (e.g., an antibiotic tolerant or resistant bacterial infection) in a subject in need thereof, in preventing a disease or infection in a subject in need thereof, in reducing the risk of developing a disease or infection in a subject in need thereof, etc. in a subject or tissue.
  • the second therapeutic agent is selected from the group consisting of a chemotherapeutic, an immunotherapy, an antioxidant, an anti- inflammatory agent, an antimicrobial, a steroid, etc.
  • the antimicrobial compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies.
  • Pharmaceutical agents include therapeutically active agents.
  • Pharmaceutical agents also include prophylactically active agents.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S.
  • the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease or infection described herein.
  • the additional pharmaceutical agents include, but are not limited to, additional antibiotics, antimicrobials, anti-proliferative agents, cytotoxic agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti- allergic agents, contraceptive agents, and pain-relieving agents.
  • additional antibiotics antibiotics
  • antimicrobials anti-proliferative agents
  • cytotoxic agents include, but are not limited to, anti-proliferative agents, cytotoxic agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti- allergic agents, contraceptive agents, and pain-relieving agents.
  • Dosages for a particular agent of the instant disclosure may be determined empirically in individuals who have been given one or more administrations of the agent.
  • Administration of an agent/compound of the present disclosure can be continuous or intermittent, depending, for example, on the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners.
  • the administration of an agent may be FIG.1 102 Docket No.: BI-11213-PCT essentially continuous over a preselected period of time or may be in a series of spaced doses.
  • Guidance regarding particular dosages and methods of delivery is provided in the literature; see, for example, U.S. Pat. Nos.4,657,760; 5,206,344; or 5,225,212.
  • kits containing agents of this disclosure for use in the methods of the present disclosure.
  • Kits of the instant disclosure may include one or more containers comprising an agent (e.g., an antibiotic) and/or composition of this disclosure.
  • the kits further include instructions for use in accordance with the methods of this disclosure.
  • these instructions comprise a description of administration of the agent to treat or prevent, e.g., an infection and/or disease.
  • the instructions comprise a description of how to administer an antibiotic to a bacterial population, and/or to a subject infected or suspected to be infected or at risk of infection with a bacteria.
  • FIG.1 103 Docket No.: BI-11213-PCT [0306]
  • the instructions generally include information as to dosage, dosing schedule, and route of administration for the intended use/treatment.
  • FIG.1A is an illustration of an environment 100 in an example implementation that is operable for antimicrobial identification and/or creation as described herein.
  • the illustrated environment 100 includes a service provider system 102, a computing device 104, a data supply 106, and a data processor 108 that are communicatively coupled, one to another directly or via a network 110.
  • functionality of the data processor 108 is illustrated as separate from the service provider system 102, the computing device 104, and the data supply 106, this functionality may be incorporated as part of FIG.1 105 Docket No.: BI-11213-PCT the service provider system 102, the computing device 104, and/or the data supply 106, further divided among other entities, and so forth.
  • an entirety of or portions of the functionality of the sequencing data processor 108 may be incorporated as part of the data supply 106, the computing device 104, or both.
  • the service provider system 102, the computing device 104, the data supply 106, the data processor 108, and the network 110 can be a single entity or multiple entities that combine to function as the respective component.
  • the data processor 108 can be a single processor or multiple processors that combine together to provide the functionality of the data processor 108.
  • the computing device 104 can be a single computing device 104 (e.g., computer) or multiple computing devices (e.g., computers) connected together as a network.
  • Computing devices that are usable as the computing device 104 to implement the service provider system 102 and the data processor 108 may be configured in a variety of ways.
  • a computing device for instance, may be configured as a desktop computer, a laptop computer, a mobile device (e.g., assuming a handheld configuration such as a tablet or mobile phone), and so forth.
  • the application manager module 112 may expose content or functionality of the data processor 108 that is accessible via the network 110 by an application 114 of the computing device 104.
  • the application 114 may be configured as a network- enabled application, a browser, a native application, and so on, that exchanges data with the service provider system 102 via the network 110.
  • the data can be employed by the application 114 to enable the user of the computing device 104 to communicate with the service provider system 102, such as to receive application updates and features when the service provider system 102 provides functionality to manage the application 114.
  • the application 114 includes functionality to input parameters for aiding in identifying and/or creating compounds as well as to analyze data generated by steps used to identify and/or create compounds.
  • the application 114 includes an interface 116 that is implemented at least partially in hardware of the computing device 104 for facilitating communication between the computing device 104 and the data processor 108.
  • the interface 116 includes functionality to receive inputs to the data processor 108 from the computing device 104 (e.g., from a user of the computing device 104) and output information, data, and so forth from the data processor 108 to the computing device 104, as will be further elaborated herein.
  • FIG.1 107 Docket No.: BI-11213-PCT [0314]
  • the environment 100 includes a screening module (e.g., a substructure screening module) 120, which is usable to screen a library of initial chemical substructures.
  • FIG. 1B is a flowchart of an example of process 150 usable to identify and/or create compounds having antimicrobial activity.
  • a library of chemical substructures is screened, for example by the screening module 120, to predict properties of the chemical substructures within the library.
  • a library of initial chemical substructures is screened, for example at 152 by the screening module 120, to predict the activity of the initial chemical substructures against a target microbe or target microbes.
  • the screening involves training an antimicrobial predictive machine learning (APML) module 126, to identify which of the chemical substructures has greater potential to exhibit antimicrobial activity against the target microbe(s). Thereafter, the library of initial chemical substructures is provided to the antimicrobial predictive machine learning module 126 to identify which of the initial chemical substructures has greater potential to exhibit antimicrobial activity against the target microbe(s).
  • the antimicrobial predictive machine learning module 126 can include one or more (e.g., at least 5, 10, 15 or more) graph neural networks (GNNs).
  • GNNs graph neural networks
  • Such an antimicrobial predictive machine learning module 126 is typically a deep learning model that infers molecular properties by representing a chemical structure as a mathematical graph.
  • the nodes or edges of the FIG.1 108 Docket No.: BI-11213-PCT mathematical graph are assigned values that are iteratively updated in a way that depends on the training.
  • the machine learning module can produce predictive results in a variety of formats.
  • the antimicrobial predictive machine learning module 126 is usable to produce a single output value between 0 and 1 for each chemical structure or substructure, representing the probability that the structure of substructure possesses a specific property of interest (e.g., antibacterial activity or cytotoxicity).
  • the TPML module 128 can be the same as or similar to the APML module 126 but trained on a different set of data.
  • HkM human primary skeletal muscle
  • HepG2 hepatocarcinoma
  • IMR-90 lung fibroblast
  • performance metrics of deep learning models are presented relative to training of the machine learning module. Each metric is detailed; for the S. aureus growth inhibition, HSkMC cytotoxicity, HepG2 cytotoxicity, and IMR-90 cytotoxicity models, benchmarking was performed using 10 models and an 80-20 split of the data. Error intervals indicate the variation in AUPRC generated from bootstrapping. For the N. gonorrhoeae growth inhibition model, benchmarking was performed using five-fold cross-validation, and standard error (SE) indicates the standard deviation across the five folds.
  • SE standard error
  • the screening module 120 are employed to screen the library of initial chemical substructures to identify which of the initial chemical substructures has greater potential to exhibit antimicrobial activity against the target microbe(s) and can be considered active chemical substructures.
  • the library of initial chemical substructures typically includes at least FIG.1 110 Docket No.: BI-11213-PCT 100,000 but not greater than 10 billion substructures.
  • the substructures are provided to the machine learning module(s) such that the module(s) determines a likelihood that each of the substructures will provide the desired property (e.g., antimicrobial activity, lack of toxicity, and so on).
  • the library of initial chemical substructures can be created and/or attained according to a variety of protocols. Many libraries of chemical substructures already exist and can be screened as discussed herein.
  • the library can also include substructures that are generated. According to one protocol, a set of atoms such as C, N, O, F, Cl, Br, S, or any combination thereof can be identified and used to create all or a subset of chemically possible and/or stable substructures having a preselected number (e.g., at least 8, 9, 10 or more, but no greater than 25, 19, 18 or less) of such atoms.
  • the library of initial substructures was provided to the machine learning module to predict the likelihood of the initial substructures exhibiting antimicrobial activity.
  • the library was screened to predict antibacterial activity against S. aureus and those substructures with prediction scores > 0.05 in the GDB and FDB databases and, due to better synthetic accessibility, > 0.1 in Enamine’s REAL Fragment database were shortlisted as active.
  • a similar analysis was run with the same prediction score thresholds for modules predicting antibacterial activity against N. gonorrhoeae, but for a subset of 45,858,026 substructures in the library that were expected to be highly accessible for synthesis. This resulted in 1,410,490 substructures (1.3%) predicted to be active against S.
  • screening of the substructures can include applying one or more filters in addition to screening for a target property (e.g., antimicrobial activity against a target microbe).
  • the filters are typically used to remove substructures from further consideration. Filtering can be accomplished using computer modules or manual techniques.
  • the TPML module 128, for example can be employed to screen substructures for predicted toxicity.
  • the initial substructures can be screened to remove substructures with undesirable chemical attributes such as PAINS or Brenk substructure by, for example, chemical attribute module 130.
  • the initial substructures can also be screened to remove substructures with similarity to other chemical compounds (e.g., known antimicrobial compounds) by, for example, chemical similarity module 132.
  • initial substructures may be removed if the initial substructures exhibit one or more of: 1) predicted cytotoxicity above a threshold; 2) PAINS or Brenk substructures; or 3) structural similarity to compounds that exhibit activity against the target microbe.
  • filters were applied to help create and/or identify structurally novel and selective substructures with no chosen chemical liabilities.
  • initial substructures were removed from further consideration if they had a Tanimoto similarity relative to one or more known antibiotics below a threshold (e.g., ⁇ 0.5).
  • the known antibiotics included a set of 559 antibacterial compounds.
  • the numbers of initial chemical substructures passing these filters to be considered active chemical substructures were 668,874 and 1,159,130 for S. aureus and N. gonorrhoeae, respectively (see FIG.4).
  • the active substructure(s) are used as guides to identify and/or create antimicrobial compounds, see 154 or FIG. 1B.
  • the FIG.1 114 Docket No.: BI-11213-PCT compounds having the active substructure(s) can be reduced by applying filters.
  • the identified compounds can be provided to the trained machine learning model and only those compounds that have above a threshold likelihood of providing antimicrobial activity may be further tested.
  • the modules 126, 128, 130 and 132 described within the screening module 120 or similar modules may be used to filter compounds, for example with a compound screening module or simply screening module, in the same way they were used to filter substructures.
  • a reference to at least one type of module can refer to one or multiple modules that have a similar or same functionality.
  • the identification module 136 can include an APML module like the APML module 126 of the screening module 120, a TPML module like the TPML module 128 of the screening module 120, a chemical attribute module like the chemical attribute module 130 of the screening module 120, and a chemical similarity module like the chemical similarity module 132 of the screening module 120. Further, filtering of compounds can be performed similarly. [0331] For identifying at least some of the antimicrobial compounds of the present disclosure, multiple filters were applied.
  • the minimum inhibitory concentrations (MICs) of these active compounds ranged from 2 to 16 ⁇ g/mL and both compounds with substructure I were equally effective against MSSA RN4220 and MRSA BAA1556 – a member of the USA300 clade associated with widespread community transmission (see FIG.9 with graphs corresponding compounds as numbered in FIG. 8).
  • the active compounds exhibited a range of selective inhibition of bacterial growth, with half-maximal inhibitory concentration (IC50) values of 2 to >128 ⁇ g/mL for substructure I-containing compounds and 32 to >128 ⁇ g/mL for substructure II-containing compounds when tested against HEK293, HepG2, HSkM and IMR90 cells (see FIG.9).
  • the therapeutic indices thus ranged between 2 to > 20 for compounds based on substructure I, and 2 to 8 for those based on substructure II.
  • a search for analogs of the compounds containing substructure I and substructure II was performed for purchasable compounds.
  • Nine analogs containing substructure I (with predicted antibacterial score > 0.1), and none containing substructure II were found.
  • Five of the nine substructure I-containing analogs were active at 32 ⁇ g/mL against both MSSA RN4220 and MRSA BAA1556; however, none exhibited higher therapeutic indices (see FIGs.10 and 11).
  • FIG.1 116 Docket No.: BI-11213-PCT [0334]
  • generative techniques are used to add chemical substructures to the active substructure(s).
  • a set of atoms such as C, N, O, F, I, Cl, Br, S, or any combination thereof can be identified and used to create all or a subset of chemically possible and/or stable substructures having a preselected number (e.g., at least 8, 9, 10 or more, but no greater than 25, 19, 18 or less) of such atoms where those substructures are suitable to be bonded to the initial active chemical substructures.
  • the generation module 136 can include an APML module like the APML module 126 of the screening module 120, a TPML module like the TPML module 128 of the screening module 120, a chemical attribute module like the chemical attribute module 130 of the screening module 120, and a chemical similarity module like the chemical similarity module 132 of the screening module 120. Further, filtering of compounds can be performed similarly. [0337] For compounds of the present disclosure, additions were made by sampling from up to 1,557,992 distinct structures containing identified organic elements (C, N, O, S, P, F, Cl, Br, I, B) from ChEMBL44, version 22 a manually curated database of bioactive molecules with drug-like properties.
  • identified organic elements C, N, O, S, P, F, Cl, Br, I, B
  • the genetic generative module employed the APML module to attain prediction scores for antibacterial activity, and then compounds FIG.1 118 Docket No.: BI-11213-PCT having prediction scores above a threshold (prediction scores > 0.3 for S. aureus and > 0.7 for N. gonorrhoeae) were successively provided as inputs for the next round of molecule generation. At each round, measures were taken to assure that all generated compounds contained either substructure I or substructure II and did not display PAINS or Brenk alerts. Additionally, compounds were penalized and/or removed if they included structures that were similar to known antibiotics or had high calculated synthetic complexity (See FIG.12B). After five rounds of selection, where each round resulted in progressively higher-scoring compounds (See FIG.
  • 1,062,567 and 518,203 compounds were generated for S. aureus and N. gonorrhoeae, respectively.
  • these compounds were further filtered based on higher thresholds for predicted antibiotic activity, predicted cytotoxicity, Tanimoto similarity to known antibiotics and the training set, and a synthetic accessibility score (based on either the SAScore45, RAScore46 and R244 score from Spaya Iktos47; see methodologies further described herein). This resulted in 428 and 285 CReM-generated compounds for S. aureus and N. gonorrhoeae, respectively (see FIGs. 14 and 15 (noting that FIG.
  • the fragment generative module can be a design-driven approach based on a generative deep learning system.
  • the system typically includes a fragment-based variational autoencoder (FVAE) trained on a library of compounds (e.g., 10,000 to 1 billion compounds).
  • FVAE architecture (see FIG. 16) typically includes a graph convolutional network encoder module in which molecular graphs of the library of compounds are encoded (e.g., as latent vectors) as well as a recurrent graph decoder FIG.1 119 Docket No.: BI-11213-PCT module, in which the latent vectors are converted back to molecular graphs.
  • the modules 126, 128, 130 and 132 described within the screening module 120 or similar modules may be used to filter compounds in the same way they were used to filter substructures.
  • a reference to at least one type of module can refer to one or multiple modules that have similar or same functionality.
  • the compound testing module 140 can include an APML module like the APML module 126 of the screening module 120, a TPML module like the TPML module 128 of the screening module 120, a chemical attribute module like the chemical attribute module 130 of the screening module 120, and a chemical similarity module like the chemical similarity module 132 of the screening module 120.
  • filtering of compounds can be performed similarly.
  • FIG.1 121 Docket No.: BI-11213-PCT
  • a threshold antibacterial score greater than 0.7 was employed to reduce the number of compounds along with a prioritization of compounds that were structurally dissimilar from each other (see FIG. 19). This resulted in 119 compounds, which were evaluated by chemical synthesis providers. Attempting the synthesis of 34 substructure I-based and 10 substructure II-based compounds resulted in the successful synthesis of four substructure I-based compounds (compounds SA1-SA4 of FIG.20, Synthesis of FIG.21) and two substructure II-based (compounds NG1-NG2 of FIG.20, Synthesis of FIG.21) with high purity (>95%).
  • aureus RN4220 at concentrations ⁇ 32 ⁇ g/mL, and one structure II-based compound, NG1, but not NG2, inhibited the growth of N. gonorrhoeae ATCC 49226 – resulting in promising working true discovery rates of 100% and 50%, respectively. Determining the MIC, IC50 values, and TIs of the active compounds as before, it was found that compounds SA1 and NG1 possessed the most favorable MIC values (both 0.5 ⁇ g/mL against S. aureus and N.
  • SA1 also inhibited the growth of 39 Gram-positive multidrug-resistant isolates from the CDC Antimicrobial Resistance Isolate Bank (ARB), including isolates from the vancomycin-intermediate S.
  • VRE vancomycin resistance enterococci
  • NG1 was also active against Neisseria meningitidis – the only other pathogenic Neisseria species – and not against the human commensal species of Neisseria cinerea or Neisseria mucosa (see FIG.25C and FIGs.23A-23C). These data indicate that de novo designed compounds exhibit antibacterial against multidrug-resistant and pathogenic strains, suggesting that the compounds may act through novel mechanisms of action to which resistance has not yet evolved. [0346] Compounds of the present disclosure were also investigated for the mechanism of action, toxicology and in vivo efficacy.
  • mice were rendered neutropenic and inflicted with skin wounds. After inoculation of ⁇ 105 CFU of MRSA USA300, each wound was topically treated with SA1 (1% w/v) six times before the wounds were excised for CFU determination 25 hours after infection.
  • the decrease in bacterial load found for SA1 was also similar to, or better than, that of complestatin and corbomycin, as well as other antibiotic candidates that have recently been discovered.
  • FIG.1 125 Docket No.: BI-11213-PCT Similar to SA1, the mechanism of action of NG1 was investigated by first examining whether the compound was bactericidal. In a time-kill experiment, NG1 exhibited concentration-dependent killing, with efficacy similar to that of azithromycin (FIG.28A). Additionally, the minimum bactericidal concentration was 1 ⁇ g/mL (FIG. 28B). In suppressor mutant generation experiments on solid agar, the frequency of resistance against NG1 was 4.3 ⁇ 10-8 at 8 ⁇ MIC.
  • NG1-resistant isolates retained susceptibility to ceftriaxone, azithromycin, and ciprofloxacin, with unchanged MICs relative to the ancestral strain (see FIG.27D).
  • the lack of cross- resistance was supported by checkboard assays demonstrating that NG1 was indifferent (neither synergistic nor antagonistic) to ceftriaxone, fosfomycin, and CCCP – indicating that NG1 does not act similarly to other cell wall- and membrane PMF-targeting antibiotics (See FIG. 27E).
  • NG1 did not alter the membrane potential in a DiSC3(5) assay (See FIG.27C).
  • NG1 was tested to determine if treatment altered membrane fluidity using a Laurdan dye assay7, where cells with decreased membrane fluidity exhibit increases in Laurdan fluorescence and vice-versa.
  • Treatment of N. gonorrhoeae cells with NG1 resulted in a modest increase in Laurdan fluorescence, suggesting that NG1 may act, in part, by decreasing membrane fluidity (FIG.28C). It was hypothesized that this would compromise membrane integrity and this hypothesis was tested by measuring the uptake of a hydrophobic fluorescent probe, 1-N-phenylnaphthylamine (NPN), which fails to cross intact outer membranes.
  • NPN 1-N-phenylnaphthylamine
  • FIG.1 127 Docket No.: BI-11213-PCT [0352]
  • SA1 and NG1 FIG.22
  • modifications were made to the position and/or type of halogen atoms (Cl or F), the position of the benzoic acid attached to the oxygen or replaced the benzene ring with a pyridine ring.
  • halogen atoms Cl or F
  • the position of the benzoic acid attached to the oxygen or replaced the benzene ring with a pyridine ring Of the ten analogs synthesized with these modifications, it was found that five exhibited the same potency as SA1 with an MIC of 0.5 ⁇ g/mL when tested against MSSA RN4220 (FIG.
  • NG1 analogs were designed and synthesized by CC4CARB (Chemistry Center for Combating Antibiotic-Resistant Bacteria), an NIAID (National Institute of Allergy and Infectious Diseases)-led partnership with RTI (Research Triangle Institute). [0389] MIC and bacterial growth inhibition assays.
  • S. aureus a bacterial suspension of ⁇ 105 CFU/mL was obtained either by performing a 1:10,000 dilution of an overnight culture, picked from a single colony, or a 1:500 dilution of an OD6000.08 suspension in fresh LB (Becton Dickinson 244620).
  • MICs were determined via broth microdilution when screening compounds, via agar dilution when confirming values for a given novel compound (e.g., NG1), or via ETEST when testing a standard-of-care antibiotic, per CLSI M100 and M07 guidelines. Prior to MIC testing, frozen stocks were passaged twice on chocolate agar plates (CAP; Hardy Diagnostics, H25). N.
  • gonorrhoeae broth microdilution was performed by first preparing the bacterial inoculum by picking FIG.1 147 Docket No.: BI-11213-PCT individual colonies from an overnight CAP, suspending in PBS to OD6000.08, and diluting the suspension 1:200 in Graver Wade media61.
  • each well of a 96- or 384-well plate was inoculated with bacteria and compound (serially diluted in DMSO) such that the final DMSO concentration in each well was ⁇ 1% and bacterial concentration was ⁇ 5 ⁇ 105 CFU/mL. Plates were incubated at 36-37°C with 5% CO2 for 20-24 hours.
  • Neisseria gonorrhoeae ETESTs bioMerieux were performed as described previously. Briefly, a sterile swab was soaked in a 0.5 McFarland standard bacterial suspension, excess fluid was removed, and the swab was used to evenly cover the entire surface of a plate of GC agar base with 1% IsoVitaleX.
  • MSSA and MRSA cells were diluted 1:10,000 from an overnight culture into fresh LB and plated into 96-well flat-bottom clear plates using 99 ⁇ L working volumes. Plates were then sealed with breathable membranes, and cells were grown to early exponential phase, OD600 ⁇ 0.01 (corresponding to ⁇ 106 CFU/mL) in a 37°C incubator with shaking at 300 rpm.
  • OD600 ⁇ 0.01 corresponding to ⁇ 106 CFU/mL
  • Human cell lines were obtained from ATCC: HEK293 (CRL-1573), HepG2 (HB-8065), HSkMCs (PCS-950-010) and IMR-90 (CCL-186).
  • HEK293 and HepG2 cells were grown to log phase in high-glucose Dulbecco’s Modified Eagle Medium (DMEM; Corning 10-013-CV) supplemented with 10% fetal bovine serum (FBS; ThermoFisher 16140071) and 1% penicillin843 streptomycin (ThermoFisher 15070063).
  • HSkMCs were grown in mesenchymal stem cell basalmedium for adipose, umbilical and bone marrow-derived MSCs (ATCC: PCS- 500-030) supplemented with ATCC’s primary skeletal muscle growth kit (ATCC: PCS- 950-040) and 1% penicillin-streptomycin.
  • N. gonorrhoeae Isolated colonies of N. gonorrhoeae ATCC 49226 were picked from an overnight plate to make a heavy suspension in PBS. The suspension was serially diluted and plated on chocolate agar to determine the initial inoculum, and 500 ⁇ L of the suspension was added to each GC agar plate containing 0, 1 ⁇ , 2 ⁇ ,4 ⁇ , or 8 ⁇ MIC of NG1.
  • pH-dependent growth inhibition Individual colonies of MSSA and MRSA were picked and grown in 2 mL liquid LB overnight at 37°C with shaking at 300 rpm. Cells were then diluted 1:10,000 into fresh liquid LB titrated to pH 7.0, 8.0 and 9.0 using ammonium hydroxide (Millipore Sigma 09859). MIC values were determined as detailed above in MIC and bacterial growth inhibition assays.
  • Laurdan membrane fluidity assay An OD600 of 0.5 cell suspension of N. gonorrhoeae ATCC 49226 was prepared in Graver Wade media.
  • a 96-well opaque flat-bottom plate (Costar Black Polystyrene Plate, 10) was prepared with 100 ⁇ L of cells in 20 ⁇ M 926 NPN in HEPES buffer added to columns 2-12.
  • 198 ⁇ L of 20 ⁇ M NPN in HEPES buffer was added, followed by 2 ⁇ L of NG1 or NG1 analog (i.e., NG2) (starting concentration of 128 ⁇ g/mL).
  • NG1 or NG1 analog i.e., NG2
  • One-hundred ⁇ L from column 1 was serially diluted across columns 2-12 to obtain a final total volume of 100 ⁇ L in each well.
  • DMSO (1%) treated cells served as the negative control.
  • FICi of ⁇ 0.5 indicates synergy, values between 0.5-4 indicate indifference, and > 4 indicates antagonism. For all combinations tested here, the FICi was 3, indicating indifference.
  • Toxicity studies Hemolysis and modified Ames genotoxicity studies were performed as described previously. All animal studies were performed at the Wyss Institute at Harvard in accordance with protocol IS00000852-6, approved by the Harvard Medical School Institutional Animal Care and Use Committee and the Committee on Microbiological Safety. To test the systemic toxicity of SA1, female C57BL/6J mice (6-12 weeks old, 22 ⁇ 2 g, Jackson Laboratory) were given increasing doses of SA1, up to 80 mg/kg.
  • a ⁇ 1.5 cm2 patch of skin was prepared on each mouse’s dorsal surface by shaving the fur, sterilizing the underlying skin, abrading the skin until visibly damaged (reddening and glistening) but not bleeding, wiping again with an alcohol swab, and allowing the skin to dry completely.
  • mice receiving SA1 1% final concentration, prepared as described above
  • n 6 mice receiving vehicle control (DMSO:PEG300:water at 10%:45%:45%)
  • n 6 mice receiving the fusidic acid positive control (0.25% final concentration in DMSO:PEG300:water at 10%:45%:45%)
  • all mice were euthanized by CO2 asphyxiation, and wounds were wiped with an alcohol pad, excised, weighed, and homogenized in 3 mL of sterile PBS using a Polytron PT10-35 with a 12 mm aggregate that was cleaned with ethanol and water between samples.
  • mice were injected with 17 ⁇ -estradiol (0.23 mg, I.P.) on Day -2 and Day 0.
  • estradiol 17 ⁇ -estradiol
  • mice were given streptomycin (1.2 mg, I.P.) and vancomycin (0.6 mg, I.P.) (1 dose on Day -2, two doses at least 5 hours apart on Day -1 and Day 0) as well as trimethoprim (0.4 g/L) in the drinking water (refreshed on Day 0).
  • the inoculum was prepared by collecting isolated colonies of N.
  • gonorrhoeae ATCC49226 from an overnight chocolate agar plate in sterile PBS to achieve an OD 0.2.
  • the vagina was first rinsed with 30 ⁇ L of 50 mM HEPES (pH 7.4) and then 20 ⁇ L of the bacterial suspension (3 ⁇ 10 6 CFU per mouse) was pipetted intravaginally while the mouse was held by the tail with paws grasping the wire cage for at least 1 minute. Serial dilutions of the bacterial suspension were plated onto chocolate agar to determine the initial inoculum.
  • the example computing device 3202 as illustrated includes a processing device 3204, one or more computer-readable media 3206, and one or more I/O interfaces 3208 that are communicatively coupled, one to another.
  • the computing device 3202 may further include a system bus or other data and command transfer system that couples the various components, one to another.
  • a system bus can include any one or combination of different bus structures, such as a memory bus or memory FIG.1 160 Docket No.: BI-11213-PCT controller, a peripheral bus, a universal serial bus, and/or a processor or local bus that utilizes any of a variety of bus architectures.
  • a variety of other examples are also contemplated, such as control and data lines.
  • the processing device 3204 is representative of functionality to perform one or more operations using hardware. Accordingly, the processing device 3204 is illustrated as including hardware elements 3210 that may be configured as processors, functional blocks, and so forth. This may include implementation in hardware as an application specific integrated circuit or other logic device formed using one or more semiconductors.
  • the hardware elements 3210 are not limited by the materials from which they are formed or the processing mechanisms employed therein.
  • processors may be comprised of semiconductor(s) and/or transistors (e.g., electronic integrated circuits (ICs)). In such a context, processor-executable instructions may be electronically executable instructions.
  • the computer-readable storage media 3206 is illustrated as including memory/storage 3212.
  • the memory/storage 3212 represents memory/storage capacity associated with one or more computer-readable media.
  • the memory/storage 3212 may include volatile media (such as random-access memory (RAM)) and/or nonvolatile media (such as read only memory (ROM), Flash memory, optical disks, magnetic disks, and so forth).
  • RAM random-access memory
  • ROM read only memory
  • Flash memory optical disks
  • magnetic disks and so forth.
  • the memory/storage 3212 may include fixed media (e.g., RAM, ROM, a fixed hard drive, and so on) as well as removable media (e.g., flash memory, a removable hard drive, an optical disc, and so forth).
  • the computer-readable media 3206 may be configured in a variety of other ways as further described below.
  • Input/output interface(s) 3208 are representative of functionality to allow a user to enter commands and information to computing device 3202, and also allow information to be presented to the user and/or other components or devices using various input/output devices.
  • input devices include a keyboard, a cursor control device (e.g., a mouse), a microphone, a scanner, touch functionality (e.g., capacitive or other sensors that are configured to detect physical touch), a camera (e.g., which may employ visible or non-visible wavelengths such as infrared frequencies to recognize movement as gestures that do not involve touch), and so forth.
  • Examples of output devices include a display device (e.g., a monitor or projector), speakers, a printer, a network card, tactile-response device, and so forth.
  • the computing device 3202 may be configured in a variety of ways as further described below to support user interaction.
  • Various techniques may be described herein in the general context of software, hardware elements, or program modules. Generally, such modules include routines, programs, objects, elements, components, data structures, and so forth that perform particular tasks or implement particular abstract data types.
  • the terms “module,” “functionality,” and “component” as used herein generally represent software, firmware, hardware, or a combination thereof.
  • module may include a hardware and/or software system that operates to perform one or more functions.
  • a module, functionality, or component may include a computer processor, a FIG.1 162 Docket No.: BI-11213-PCT controller, or another logic-based device that performs operations based on instructions stored on a computer-readable storage medium, such as a computer memory.
  • the computer-readable storage medium may be tangible and non-transitory.
  • a module, functionality, or component may include a hard-wired device that performs operations based on hard-wired logic of the device.
  • Various modules, systems, and components shown in the attached figures may represent the hardware that operates based on software or hardwired instructions, the software that directs hardware to perform the operations, or a combination thereof.
  • An implementation of the described modules and techniques may be stored on or transmitted across some form of computer-readable media.
  • the computer-readable media may include a variety of media that may be accessed by the computing device 3202.
  • computer-readable media may include “computer-readable storage media” and “computer-readable signal media.”
  • Computer-readable storage media may refer to media and/or devices that enable persistent and/or non-transitory storage of information in contrast to mere signal transmission, carrier waves, or signals per se.
  • computer-readable storage media refers to non-signal bearing media.
  • the computer-readable storage media includes hardware such as volatile and non-volatile, removable and non-removable media, and/or storage devices implemented in a method or technology suitable for storage of information such as computer readable instructions, data structures, program modules, logic elements/circuits, or other data.
  • Signal media typically may embody computer readable instructions, data structures, program modules, or other data in a modulated data signal, such as carrier waves, data signals, or other transport mechanism.
  • Signal media also include any information delivery media.
  • modulated data signal means a signal that has one or more of its characteristics set or changed in such a manner as to encode information in the signal.
  • communication media include wired media such as a wired network or direct-wired connection, and wireless media such as acoustic, RF, infrared, and other wireless media.
  • hardware elements 3210 and computer-readable media 3206 are representative of modules, programmable device logic and/or fixed device logic implemented in a hardware form that may be employed in some embodiments to implement at least some aspects of the techniques described herein, such as to perform one or more instructions.
  • Hardware may include components of an integrated circuit or on-chip system, an application-specific integrated circuit (ASIC), a field-programmable gate array (FPGA), a complex programmable logic device (CPLD), and other implementations in silicon or other hardware.
  • ASIC application-specific integrated circuit
  • FPGA field-programmable gate array
  • CPLD complex programmable logic device
  • hardware may operate as a processing device that performs program tasks defined by instructions and/or logic FIG.1 164 Docket No.: BI-11213-PCT embodied by the hardware as well as a hardware utilized to store instructions for execution, e.g., the computer-readable storage media described previously.
  • FIG.1 164 Docket No.: BI-11213-PCT embodied by the hardware as well as a hardware utilized to store instructions for execution, e.g., the computer-readable storage media described previously.
  • Combinations of the foregoing may also be employed to implement various techniques described herein. Accordingly, software, hardware, or executable modules may be implemented as one or more instructions and/or logic embodied on some form of computer-readable storage media and/or by one or more hardware elements 3210.
  • the computing device 3202 may be configured to implement particular instructions and/or functions corresponding to the software and/or hardware modules.
  • implementation of a module that is executable by the computing device 3202 as software may be achieved at least partially in hardware, e.g., through use of computer- readable storage media and/or hardware elements 3210 of the processing device 3204.
  • the instructions and/or functions may be executable/operable by one or more articles of manufacture (for example, one or more computing devices 3202 and/or processing devices 3204) to implement techniques, modules, and examples described herein.
  • the techniques described herein may be supported by various configurations of the computing device 3202 and are not limited to the specific examples of the techniques described herein. This functionality may also be implemented all or in part through use of a distributed system, such as over a “cloud” 3214 via a platform 3216 as described below.
  • the platform 3216 may also serve to abstract scaling of resources to provide a corresponding level of scale to encountered demand for the resources 3218 that are implemented via the platform 3216. Accordingly, in an interconnected device embodiment, implementation of functionality described herein may be distributed throughout the system 3200. For example, the functionality may be implemented in part on the computing device 3202 as well as via the platform 3216 that abstracts the functionality of the cloud 3214.
  • References related to antimicrobial discovery include the following: 1) ChempropYang, K., Swanson, K., Jin, W., Coley, C., Eiden, P., Gao, H., Guzman-Perez, A., Hopper, T., Kelley, B., Mathea, M., et al. (2019).
  • the generative module is selected from a genetic generative module, a fragment generative module, or both.
  • the fragment generative module may comprise a fragment-based variational autoencoder as described above and /or as depicted in Fig.16.
  • the screening of the library of initial chemical substructures includes training the substructure screening module to identify which of the chemical substructures has greater potential to exhibit antimicrobial activity against the target microbe.
  • the substructure screening module is a machine learning module.
  • the machine learning module includes one or more graph neural networks (GNNs) representing a deep learning model that infers molecular properties by representing chemical structures as mathematical graphs.
  • GNNs graph neural networks
  • the machine learning module uses message passing operations to assign values to nodes and/or edges of mathematical graphs and update those values iteratively based upon training of the machine learning module.
  • (A7) For the method denoted as (A4), (A5), or (A6) the machine learning module produces a single output value for each chemical substructure of between 0 and 1, FIG.1 168 Docket No.: BI-11213-PCT representing a probability that each chemical substructure of the library of chemical substructures possesses antimicrobial activity against the target microbes.
  • (A8) For the method denoted as any of (A1) through (A7) the library of initial chemical substructures typically, e.g. may, include at least 100,000 but not greater than 10 billion substructures.
  • the screening of the library of initial substructures may include removing initial substructures of the library of initial substructures, wherein the initial substructures exhibit one or more of: 1) predicted cytotoxicity above a threshold; 2) PAINS or Brenk substructures; or 3) structural similarity to compounds that exhibit activity against the target microbe.
  • the initial substructures exhibit one or more of: 1) predicted cytotoxicity above a threshold; 2) PAINS or Brenk substructures; or 3) structural similarity to compounds that exhibit activity against the target microbe.
  • the at least one active chemical substructure is provided to the generative module and the generative module includes an algorithm that provides a computational framework that starts with at least one active chemical substructure and generates the candidate compounds by adding, replacing, or deleting atoms and functional groups.
  • the at least one active chemical substructure is provided to the generative module, which is based on a generative deep learning system.
  • the generative module employs a set of atoms that include C, N, O, Cl, or any combination thereof to create all or a subset of chemically possible and/or stable substructures having a preselected number (e.g., at least 8, 9, 10 or more, but no greater than 25, 19, 18 or less) of such atoms, the chemically possible substructures being bonded to the at least one active chemical substructure.
  • the set of atoms includes at least two of F, Br, or S.
  • the system denoted as (B1) or (B2) may comprise, for example, a substructure screening module configured to screen a library of initial chemical substructures to identify at least one active chemical substructure from the initial chemical substructures; wherein the substructure screening module predicts the activity of the active chemical substructure against a target microbe; a generative module configured to receive the at least one active chemical substructure and create a plurality of candidate compounds; and a compound screening module configured to screen the plurality of candidate compounds to identify a target set of compounds.
  • the system denoted as (B1) through (B3) may enable the target set of compounds to be tested to determine the activity of the target set of compounds against the target microbe, the target set of compounds being a subset of the plurality of candidate compounds, and the target set of compounds having the active chemical substructure.
  • the present application also discloses a computer-readable / machine- readable medium comprising instructions which, when implemented by a processor, cause the processor to perform any of the methods described herein, including the methods denoted as any of (A1) through (A14), with or without a step of testing the target set of compounds.
  • (C1) A pharmaceutical composition for treating or preventing a microbial infection in a subject comprising: a compound of structure VI as follows: FIG.1 171 Docket No.: BI-11213-PCT
  • R 1 is independently selected from H, halogen, or C1-C2 alkyl
  • R 2 is independently selected from H or halogen
  • R 3 is independently selected from H or halogen
  • R 4 is independently selected from H or C 1 -C 2 alkyl
  • R 5 is independently selected from H, or halogen
  • R 6 is independently selected from H, alkoxy or halogen
  • A- is an anion; or a pharmaceutically acceptable salt and/or stereoisomer thereof.
  • (C3) The pharmaceutical composition of (C1) or (C2), wherein the compound of structure VI is defined by at least two or any possible combination of the following: 1) FIG.1 172 Docket No.: BI-11213-PCT R 1 is methyl or Cl; 2) R 2 is Cl; 3) R 3 is Cl or F; 4) R 4 is methyl; 5) R 5 is Cl; 6) R 6 is methoxy or Cl; 7) R 7 is methyl; 8) R 1 is H; 9) R 2 is H; 10) R 3 is H; 11) R 4 is H; 12) R 5 is H; 13) R 6 is H; and/or 14) R 7 is H.
  • FIG.1 175 Docket No.: BI-11213-PCT
  • R 1 is independently selected from H or halogen;
  • R 2 is independently selected from H or C 1 -C 2 alkyl;
  • R 3 is independently selected from H or OH;
  • R 4 is independently selected from H or OH;
  • R 5 is independently selected from H, OH or alkoxy.
  • (C13) The pharmaceutical composition of (C11) or (C12), wherein the compound of structure VII is defined by at least two or any possible combination of the following: 1) R 1 is Br; 2) R 2 is methyl; 3) R 3 is OH; 4) R 4 is OH; 5) R 5 is OH; 6) R 5 is methoxy; 7) R 1 is H; 8) R 2 is H; 9) R 3 is H; 10) R 4 is H; and/or 11) R 5 is H.
  • (C14) The pharmaceutical composition of (C11), (C12) or (C13), wherein at least two or all three of R 3 -R 5 are OH.
  • (C15) The pharmaceutical composition of (C11), (C12) or (C13), wherein the compound of structure VII is selected from at least one of the following: benzene-1,2,3-triol; FIG.1 179 Docket No.: BI-11213-PCT
  • FIG.1 180 Docket No.: BI-11213-PCT [0461] (C16) The pharmaceutical composition of any one of (C11)-(C15), wherein the microbial infection is resistant to one or more antimicrobial agents. [0462] (C17) The pharmaceutical composition of (C16), wherein the one or more antimicrobial agents are selected from amoxicillin, ampicillin, nafcillin, piperacillin, or penicillin G. [0463] (C18) The pharmaceutical composition of any one of (C11)-(C17), further comprising a pharmaceutically acceptable carrier, the pharmaceutical carrier combined with a therapeutically effective amount of the compound to form a solid, gel, suspension, or liquid dosage form.
  • a pharmaceutically acceptable carrier the pharmaceutical carrier combined with a therapeutically effective amount of the compound to form a solid, gel, suspension, or liquid dosage form.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Theoretical Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Computing Systems (AREA)
  • Mathematical Physics (AREA)
  • Computational Linguistics (AREA)
  • Data Mining & Analysis (AREA)
  • Evolutionary Computation (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • General Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Software Systems (AREA)
  • Artificial Intelligence (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Pharmaceutical compositions are disclosed. The pharmaceutical compositions include an antimicrobial compound. The compositions can also include a pharmaceutically acceptable carrier. Discovery methods for discovery of antimicrobial compounds are also disclosed. The discovery methods employ a trained machine learning model to identify substructures of chemical compounds that are predicted to exhibit antimicrobial activity. Antimicrobial activity of known compounds can be discovered and antimicrobial compounds with identified substructures can be generated and/or synthesized.

Description

Antimicrobials and Discovery Thereof GOVERNMENT RIGHTS [0001] This invention was made with government support under Grant Nos. AI168451, AI146194, CA921641, AI182474, and 75N93021C00002 awarded by the National Institutes of Health, and Grant No. HDTRA1-22-1-0032 awarded by the Department of Defense. The government has certain rights in the invention. The Swiss National Science Foundation language should follow. BACKGROUND [0002] There is a continuing significant need for the development of antimicrobial compounds to treat (i.e., help eradicate) and/or prevent bacterial and viral infections. This need is becoming more and more acute as pathogens that cause such infections evolve and become resistant to currently existing antimicrobial compounds. As an example, bacterial pathogens such as Staphylococcus aureus and Neisseria gonorrhoeae have been identified as high priority targets by the U.S. Centers for Disease Control and Prevention (the “CDC”) due to widespread incidence of antimicrobial resistance. [0003] Notably, difficulties in identifying and developing antimicrobial compounds tend to hinder the development of such compounds. As an example, the cost of developing antimicrobial compounds is quite high. As a further example, traditional techniques for identifying and/or developing antimicrobial compounds are often quite slow. As such, there is a significant need for the identification and development of FIG.1 1 Docket No.: BI-11213-PCT antimicrobial compounds. There is also a significant need for improved techniques that are useful in the identification and development of antimicrobial compounds. SUMMARY [0004] Disclosed are pharmaceutical compositions for treating or preventing a microbial infection in a subject. According to one aspect of the disclosure, the compositions include a compound of structure VI as defined herein. According to another aspect of the disclosure, the compositions include a compound of structure VII as defined herein. According to another aspect of the disclosure, the compositions include a compound of substructure I bonded to Z1 and substructure Z2 as follows: R1A H wherein: FIG.1 2 Docket No.: BI-11213-PCT R1 – R4 are independently selected from C or N with at least two, more typically at least three, and quite possibly all four of R1 - R4 being C; R5 – R9 are independently selected from C or N with at least three, more typically at least four, and quite possibly all five of R5 - R9 being C; R1A – R4A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, OH or halogen, with R1A – R4A only being nothing where, respectively, R1 – R4 is selected as N; and R5A – R9A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, OH, or halogen, with R5A – R9A only being nothing if, respectively, R5 – R9 is selected as N; Z1 is H or CH3; and Z2 is a substructure as follows: R11A R 12A wherein: R10 is selected from CH2, NH, S or O, but is typically either S or O; R11 – R15 are independently selected from C or N, with no more than two of R11 – R15 being N, and more typically no more than one of R11 – R15 being N; FIG.1 3 Docket No.: BI-11213-PCT R11A – R15A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, carboxyl, OH or halogen, with R11A – R15A only being nothing if, respectively, R11 – R15 is selected as N; at least one of R11A – R15A is carboxyl; and at least two of R11A – R15A are H; or a pharmaceutically acceptable salt and/or stereoisomer thereof. [0005] According to another aspect of the disclosure, the compositions include the compound according to substructure I according to descriptions herein, and Z1 and substructure Z2 according to descriptions herein, wherein: R1 – R4 are C; R5 – R7 are C, and R8 – R9 are independently selected from C or N, with only one of R8 or R9 being N, if any; R10 is S or O but is typically O. R1A – R4A are independently selected from H or halogen, with only one, if any, of R1A – R4A being halogen, and the halogen is selected from F, Br, and Cl; R5A – R7A are independently selected from H or halogen, with only one, if any, of R5A – R7A being halogen, and the halogen is selected from F, Br, and Cl; and R8A – R9A are independently selected from nothing, H or halogen with only one, if any, of R8A – R9A being halogen and the halogen being selected from F, Br and Cl and with R8A or R9A being nothing if, respectively, R8 or R9 is N. [0006] According to another aspect of the disclosure, the compositions include the compound according to substructure I according to descriptions herein, and Z1 and substructure Z2 according to descriptions herein, wherein: FIG.1 4 Docket No.: BI-11213-PCT R1 – R4 are C; R5 – R9 are C; R1A, R2A, and R4A are H, and R3A is H or halogen, the halogen being selected from F and Cl; R5A, R6A, R8A and R9A are H; and R7A is H or halogen, the halogen being selected from F and Cl. [0007] According to another aspect of the disclosure, the compositions include the compound according to substructure I according to descriptions herein, and Z1 and substructure Z2 according to descriptions herein, wherein at least one, two, three, or any possible combination of the following: 1) at least two of R1A – R4A are H; 2) at least three of R1A – R4A are H; 3) at least one of R1A – R4A is halogen; 4) at least two of R1A – R4A are halogen; 5) at least two of R5A – R9A are H; 6) at least three of R5A – R9A are H; 7) at least one of R5A – R9A is halogen; 8) at least two of R5A – R9A are halogen; and/or 9) at least three of R5A – R9A are halogen. [0008] According to another aspect of the disclosure, the compositions include the compound according to substructure I according to descriptions herein, and Z1 and substructure Z2 according to descriptions herein, wherein: Z1 is H; and substructure Z2 is as follows: R10 is selected from S or O; R11 – R15 are independently selected from C or N, with no more than one of R11 – R15 being N; FIG.1 5 Docket No.: BI-11213-PCT R11A – R15A are independently selected from nothing, H, CH3, and carboxyl, with R11A – R15A only being nothing if, respectively, R11 – R15 is selected as N; one of R11A – R15A is carboxyl; and at least three of R11A – R15A are H. [0009] According to another aspect of the disclosure, the compositions include the compound according to substructure I according to descriptions herein, and Z1 and substructure Z2 according to descriptions herein, wherein: Z1 is H; and substructure Z2 is as follows: R10 is O; R11 – R15 are C; R11A – R15A are independently selected from H and carboxyl; one of R11A – R15A is carboxyl; and four of R11A – R15A are H. [0010] According to further aspects of compositions for treating the microbial infection and including a compound having substructure I, Z1, and substructure Z2, the microbial infection is resistant to one or more antimicrobial agents and/or the microbial infection is a bacterial infection. [0011] According to further aspects of compositions for treating the microbial infection and including a compound having substructure I, Z1, and substructure Z2: i) the composition further comprises a pharmaceutically acceptable carrier, the pharmaceutical carrier combined with a therapeutically effective amount of the compound to form a solid, gel, suspension or liquid dosage form; and/or ii) the FIG.1 6 Docket No.: BI-11213-PCT composition is provided in a dosage form that contains from about 0.001 mg/kg to about 1000 mg/kg of the compound. [0012] According to a further aspect of the disclosure, the compositions include a compound of substructure II bonded to substructure Y1 as follows: Substructure II O Y1 wherein: R1 – R5 are independently selected from C or N with at least three, more typically at least four, and quite possibly all five of R1 - R5 being C; R1A – R5A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, OH or halogen, with R1A – R5A only being nothing if, respectively, R1 – R5 is selected as N; and substructure Y1 is as follows: FIG.1 7 Docket No.: BI-11213-PCT R12 O R10 R6 – R10 are independently selected from H, CH3, and halogen with no more than one of R6 – R10 being CH3, no more than three, and more typically no more than two of R6 – R10 being halogen, and at least two, and more typically at least three of R6 – R10 being H; R11 is selected from CH2, or C2-C4 alkyl or alkylene, and is typically C2H4; and R12 is selected from H, CH3, or C2-C4 alkyl or alkylene, and is typically CH3; or a pharmaceutically acceptable salt and/or stereoisomer thereof. [0013] According to another aspect of the disclosure, the compositions include the compound according to substructure II according to descriptions herein, having substructure Y1 according to descriptions herein, wherein at least one, two, three, or any possible combination of the following: 1) at least two of R1A – R5A are H; 2) at least three of R1A – R5A are H; 3) at least one of R1A – R5A is halogen; and/or 4) at least two of R1A – R5A are halogen. [0014] According to another aspect of the disclosure, the compositions include the compound according to substructure II according to descriptions herein, having FIG.1 8 Docket No.: BI-11213-PCT substructure Y1 according to descriptions herein, wherein, for each selection of halogen, the halogen is Cl, F, or Br. [0015] According to another aspect of the disclosure, the compositions include the compound according to substructure II according to descriptions herein, having substructure Y1 according to descriptions herein, wherein, any combination of the following: three of R6 – R10 are H; two of R6 – R10 are halogen; the halogen(s) of R6 – R10 are selected from F, Cl and Br; the halogen(s) of R6 – R10 are Cl; or R11 is C2H2, and the halogen(s), if any, are at R8 and/or R9. [0016] According to another aspect of the disclosure, the compositions include the compound according to substructure II according to descriptions herein, having substructure Y1 according to descriptions herein, wherein substructure Y1 is as follows: R10 wherein: R6 – R9 are independently selected from C or N, with typically at least one, two, or three of R6 – R9 being N, and one or two of R6 – R9 being C; and R10 is independently selected from H, CH3, or CH2CH3 and is bonded to one of R6 – R9, which has been independently selected as N. [0017] According to a further aspect of the present disclosure, there is disclosed a method of identifying or creating one or more compounds having antimicrobial activity or other activity. The method includes screening a library of initial chemical FIG.1 9 Docket No.: BI-11213-PCT substructures to identify at least one active chemical substructure from the initial chemical substructures, the screening of the library of initial chemical substructures being performed by a screening module (e.g., a substructure screening module), which predicts the activity of the active chemical substructure against a target microbe. The method further includes providing the at least one active chemical substructure to a generative module to create a plurality of candidate compounds. Still further, the method includes screening the plurality of candidate compounds to identify a target set of compounds, the screening of the plurality of candidate compounds being performed by a compound screening module. The method can also include testing the target set of compounds to determine the activity of the target set of compounds against the target microbe, the target set of compounds being a subset of the plurality of candidate compounds, the target set of compounds having the active chemical substructure. [0018] According to various aspects of the method, one or any combination of the following: i) the generative module is selected from a genetic generative module, a fragment generative module, or both; ii) the screening of the library of initial chemical substructures includes training the substructure screening module to identify which of the chemical substructures has greater potential to exhibit antimicrobial activity against the target microbe; iii) the substructure screening module is a machine learning module, wherein the machine learning module includes one or more graph neural networks (GNNs) representing a deep learning model that infers molecular properties by representing chemical structures as mathematical graphs; iv) the machine learning module uses message passing operations to assign values to nodes and/or edges of mathematical graphs and update those values iteratively based upon training of the FIG.1 10 Docket No.: BI-11213-PCT machine learning module; v) the machine learning module produces a single output value for each chemical substructure of between 0 and 1, representing a probability that each chemical substructure of the library of chemical substructures possesses antimicrobial activity against the target microbes; vi) the library of initial chemical substructures typically includes at least 100,000 but not greater than 10 billion substructures. [0019] According to additional or alternative aspects of the method, the screening of the library of initial substructures includes removing initial substructures of the library of initial substructures wherein the initial substructures exhibit one or more of: 1) predicted cytotoxicity above a threshold; 2) PAINS or Brenk substructures; or 3) structural similarity to compounds that exhibit activity against the target microbe. [0020] According to additional or alternative aspects of the method, the at least one active chemical substructure is provided to the generative module and the generative module includes an algorithm that provides a computational framework that starts with at least one active chemical substructure and generates the candidate compounds by adding, replacing, or deleting atoms and functional groups. [0021] According to another additional or alternative aspect, the generative module employs a set of atoms that includes C, N, O, Cl, or any combination thereof to create all or a subset of chemically possible and/or stable substructures having a preselected number (e.g., at least 8, 9, 10 or more, but no greater than 25, 19, 18 or less) of such atoms, the chemically possible substructures being bonded to the at least one active chemical substructure. FIG.1 11 Docket No.: BI-11213-PCT [0022] This Summary introduces a selection of concepts in a simplified form that are further described below in the Detailed Description. As such, this Summary is not intended to identify essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter. BRIEF DESCRIPTION OF THE DRAWINGS [0023] The detailed description is described with reference to the accompanying figures. [0024] FIG. 1A is an illustration of an example environment that is operable to implement aspects of discovery (e.g., identification and/or generation) of chemical compounds (e.g., antimicrobial compounds). [0025] FIG. 1B depicts a flowchart of an example implementation of discovery of chemical compounds (e.g., antimicrobial compounds). [0026] FIG. 2A depicts a table of exemplary data useful for discovery of chemical compounds (e.g., antimicrobial compounds). [0027] FIG. 2B depicts an example of a map of chemical space useful in aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0028] FIG. 3 depicts an example of graphs of data that describe results of predictive scores of a machine learning module useful in aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0029] FIG. 4 is a visual depiction of screening of substructures/fragments useful in aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0030] FIG. 5 depicts an example of graphs of data useful in aspects of discovery of chemical compounds (e.g., antimicrobial compounds). FIG.1 12 Docket No.: BI-11213-PCT [0031] FIGs.6A-6M and 7A-7D depict examples of compounds predicted to be active by a machine learning model (left) as compared to known antibiotics (right) along with Tanimoto similarity scores (middle) according to aspects of discovery and/or generation of chemical compounds (e.g., antimicrobial compounds). [0032] FIG.8 depicts examples of chemical substructures and chemical compounds in accordance with aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0033] FIG.9 depicts a graph of exemplary data resulting from testing of the chemical compounds of FIG.8 in accordance with aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0034] FIG. 10 depicts examples from testing of analogs of chemical compounds of FIG. 8 tested to be active or inactive according to example standards of discovery of chemical compounds (e.g., antimicrobial compounds). [0035] FIG.11 depicts a graph of exemplary data resulting from testing of the chemical compounds of FIG.10 in accordance with aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0036] FIG. 12A is flowchart of an exemplary algorithm useful for generation of compounds in accordance with an aspect of discovery of chemical compounds (e.g., antimicrobial compounds). [0037] FIG.12B is an example of a visual depiction of exemplary data useful in aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0038] FIG.13 is an example of a visual depiction of exemplary data useful in aspects of discovery of chemical compounds (e.g., antimicrobial compounds). FIG.1 13 Docket No.: BI-11213-PCT [0039] FIG. 14 depicts examples of chemical compounds (e.g., antimicrobial compounds) generated according to aspects of the present disclosure. [0040] FIG. 15 depicts an example of a map of chemical space useful in aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0041] FIG.16 is a schematic diagram of at least a portion of an exemplary generative module according to aspects of the present disclosure. [0042] FIG. 17 depicts examples of chemical compounds (e.g., antimicrobial compounds) generated according to aspects of the present disclosure. [0043] FIG.18 is an example of a visual depiction of exemplary data useful in aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0044] FIG.19 is a visual depiction of down-selection of generated compounds useful in aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0045] FIG. 20 depicts examples of chemical compounds (e.g., antimicrobial compounds) generated according to aspects of the present disclosure. [0046] FIG. 21 depicts example synthesis steps useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0047] FIG.22 depicts a graph of exemplary data resulting from testing of the chemical compounds of FIG.20 in accordance with aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0048] FIGs.23A-23C depict tables of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0049] FIG. 24 depicts a table of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). FIG.1 14 Docket No.: BI-11213-PCT [0050] FIG. 25A is a depiction of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0051] FIG. 25B depicts a graph of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0052] FIG. 25C depicts a graph of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0053] FIGs. 26A and 26B depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0054] FIGs. 26C and 26D depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0055] FIGs. 26E depicts a graph of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0056] FIGs. 27A and 27B depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0057] FIGs. 27C and 27D depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0058] FIG. 27E depicts graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0059] FIGs. 28A and 28B depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0060] FIGs. 28C and 28D depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). FIG.1 15 Docket No.: BI-11213-PCT [0061] FIGs. 28E and 28F depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0062] FIGs. 29A and 29B depict examples of analogs of chemical compounds (e.g., antimicrobial compounds) designed according to aspects of the present disclosure. [0063] FIG. 29C depicts a graph of exemplary data resulting from testing of the chemical compounds of FIGs.29A and 29B in accordance with aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0064] FIG. 30A depicts examples of chemical compounds (e.g., antimicrobial compounds) generated according to aspects of the present disclosure. [0065] FIG. 30B depicts a graph of exemplary data resulting from testing of the chemical compounds of FIG.30A in accordance with aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0066] FIG. 30C depicts a graph of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0067] FIG. 30D and 30E depict graphs of data useful for aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0068] FIG. 31A depicts examples of chemical compounds (e.g., antimicrobial compounds) discovered (e.g., designed) according to aspects of the present disclosure. [0069] FIG. 31B depicts a table of data and chemical variations related to chemical compounds (e.g., antimicrobial compounds) generated according to aspects of the present disclosure. [0070] FIG. 31C depicts examples of chemical compounds (e.g., antimicrobial compounds) generated according to aspects of the present disclosure. FIG.1 16 Docket No.: BI-11213-PCT [0071] FIG. 31D depicts a graph of exemplary data resulting from testing of the chemical compounds of FIG. 31B and 31C and other compounds in accordance with aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0072] FIG. 32 is an illustration of an example environment that is operable to implement aspects of discovery of chemical compounds (e.g., antimicrobial compounds). [0073] FIG.33A depicts a table of compounds and respective data for those compounds in accordance with aspects of the present disclosure. [0074] FIG.33B depicts a table of compounds and respective data for those compounds in accordance with aspects of the present disclosure. [0075] FIG.33C depicts a table of compounds and respective data for those compounds in accordance with aspects of the present disclosure. [0076] FIG.34 depicts a table of data for compounds in accordance with aspects of the present disclosure. [0077] FIG.35 depicts graphs of exemplary data resulting from testing of the chemical compounds in accordance with aspects of discovery of the present disclosure. [0078] FIG.36 depicts a table of data for compounds in accordance with aspects of the present disclosure. [0079] FIG.37 depicts graphs of exemplary data resulting from testing of the chemical compounds in accordance with aspects of discovery of the present disclosure. [0080] FIG.38 depicts a graph of exemplary data resulting from testing of the chemical compounds in accordance with aspects of discovery of the present disclosure. FIG.1 17 Docket No.: BI-11213-PCT DETAILED DESCRIPTION [0081] The current disclosure relates, at least in part, to the discovery (e.g., identification, development and/or generation) of antimicrobial compounds. In one aspect, the current disclosure relates to antimicrobial compounds and substructures of antimicrobial compounds discovered (e.g., identified and/or generated) using in silico methods that employ machine learning to achieve robust and accurate predictive identification of effective antimicrobial compounds and/or substructures. Substructures and compounds can be so identified from compound and/or substructure (also referred to herein as fragments) databases or from generation of compounds and/or antimicrobial compounds or both. The current disclosure also relates, at least in part to the discovery (e.g., identification and/or generation) of substructures that form a part of the antimicrobial compounds. Development of antimicrobial compounds that include and/or are based on the substructures show that the substructures, in certain circumstances, define new classes of antimicrobial compounds. [0082] Substructure I [0083] One substructure developed and/or identified in accordance with the present disclosure is substructure I shown below: FIG.1 18 Docket No.: BI-11213-PCT R1A H [0084] Compounds having substructure I have been found to have particularly desirable activity against Staphylococcus aureus but are not so limited unless specifically stated. [0085] Substructure I allows for multiple variations in an embodiment I as follows: R1 – R4 are independently selected from C or N with at least two, more typically at least three, and quite possibly all four of R1 - R4 being C; R5 – R9 are independently selected from C or N with at least three, more typically at least four, and quite possibly all five of R5 - R9 being C; R1A – R4A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, OH or halogen, with R1A – R4A only being nothing where, respectively, R1 – R4 is selected as N; and FIG.1 19 Docket No.: BI-11213-PCT R5A – R9A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, OH, or halogen, with R5A – R9A only being nothing if, respectively, R5 – R9 is selected as N. [0086] Substructure I further allows for multiple variations in an embodiment II as follows: R1 – R4 are C; R5 – R7 are C, and R8 – R9 are independently selected from C or N, with only one of R8 or R9 being N, if any; R1A – R4A are independently selected from H or halogen, with only one, if any, of R1A – R4A being halogen, and the halogen is selected from F, Br, and Cl; and R5A – R7A are independently selected from H or halogen, with only one, if any, of R5A – R7A being halogen, and the halogen is selected from F, Br, and Cl; R8A – R9A are independently selected from nothing, H or halogen, with only one, if any, of R8A – R9A being halogen and the halogen being selected from F, Br and Cl, and with R8A or R9A being nothing if, respectively, R8 or R9 is N. [0087] Substructure I also allows for multiple variations in an embodiment III as follows: R1 – R4 are C; R5 – R9 are C; R1A, R2A, and R4A are H, and R3A is H or halogen, the halogen being selected from F and Cl; R5A, R6A, R8A and R9A are H; and FIG.1 20 Docket No.: BI-11213-PCT R7A is H or halogen, the halogen being selected from F, Br, and Cl or, more particularly, from F and Cl. [0088] In defining substructure I, any of the embodiments I, II and III can be, as appropriate, further defined by at least one, two, three, or any possible combination of the following: 1) at least two of R1A – R4A are H; 2) at least three of R1A – R4A are H; 3) at least one of R1A – R4A is halogen; 4) at least two of R1A – R4A are halogen; 5) at least two of R5A – R9A are H; 6) at least three of R5A – R9A are H; 7) at least one of R5A – R9A is halogen; 8) at least two of R5A – R9A are halogen; and/or 9) at least three of R5A – R9A are halogen. [0089] For each selection of halogen of the substructure I, the halogen can be Cl, Fl, Br, or any combination thereof unless otherwise indicated. [0090] It is understood that substructure I includes all stereoisomers thereof. [0091] Substructure II [0092] Another substructure developed and/or identified in accordance with the present disclosure is substructure II shown below: FIG.1 21 Docket No.: BI-11213-PCT Substructure II O [0093] activity against Neisseria gonorrhoeae but are not so limited unless specifically stated. [0094] Substructure II allows for multiple variations in an embodiment I as follows: R1 – R5 are independently selected from C or N with at least three, more typically at least four, and quite possibly all five of R1 -R5 being C; and R1A – R5A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, OH or halogen, with R1A – R5A only being nothing if, respectively, R1 – R5 is selected as N. [0095] In defining substructure II, at least one, two, three, or any possible combination of the following: 1) at least two of R1A – R5A are H; 2) at least three of R1A – R5A are H; 3) at least one of R1A – R5A is halogen; and/or 4) at least two of R1A – R5A are halogen. [0096] For each selection of halogen of the substructure II, the halogen can be Cl, F, Br, or any combination thereof unless otherwise indicated. [0097] It is understood that substructure II includes all stereoisomers thereof. FIG.1 22 Docket No.: BI-11213-PCT [0098] Antimicrobial Compounds [0099] Antimicrobial compounds of the present disclosure include compounds that include substructure I and substructure II as well as additional compounds. [0100] Compounds with Substructure I [0101] Antimicrobial compounds that include substructure I will typically include compounds that have Z1 and substructure Z2 bonded to substructure I as shown below: [0102] R1A H However, it is contemplated that Z1 and/or substructure Z2 could be bonded to substructure I at different locations. [0103] According to an aspect of the present disclosure, substructure Z2 is substructure Z21 as follows: FIG.1 23 Docket No.: BI-11213-PCT R11A R12A [0104] In an I, Z1 is H or CH3, typically H, and substructure Z2 is substructure Z21, which allows for variation as follows: R10 is selected from CH2, NH, S or O, but is typically either S or O; R11 – R15 are independently selected from C or N, with no more than two of R11 – R15 being N, and more typically no more than one of R11 – R15 being N; R11A – R15A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, carboxyl, OH or halogen, with R11A – R15A only being nothing if, respectively, R11 – R15 is selected as N; at least one of R11A – R15A is carboxyl; and at least two of R11A – R15A are H. [0105] In an embodiment B of compounds that include substructure I, Z1 is H and substructure Z2 is substructure Z21, which allows for variation as follows: R10 is selected from S or O; R11 – R15 are independently selected from C or N, with no more than one of R11 – R15 being N; FIG.1 24 Docket No.: BI-11213-PCT R11A – R15A are independently selected from nothing, H, CH3, and carboxyl with R11A – R15A only being nothing if, respectively, R11 – R15 is selected as N; one of R11A – R15A is carboxyl; and at least three of R11A – R15A are H. [0106] In an embodiment C of compounds that include substructure I, Z1 is H and substructure Z2 is substructure Z21, which allows for variation as follows: R10 is O; R11 – R15 are C; R11A – R15A are independently selected from H and carboxyl; one of R11A – R15A is carboxyl; and four of R11A – R15A are H. [0107] It is contemplated that any of the variations of the embodiments of substructure I can be matched or combined with any of the embodiments of Z1 and substructure Z2. The present disclosure specifically contemplates compounds as follows: embodiment I of substructure I with embodiment A of Z1 and substructure Z2; embodiment I of substructure I with embodiment B of Z1 and substructure Z2; embodiment I of substructure I with embodiment C of Z1 and substructure Z2; embodiment II of substructure I with embodiment A of Z1 and substructure Z2; embodiment II of substructure I with embodiment B of Z1 and substructure Z2; embodiment II of substructure I with embodiment C of Z1 and substructure Z2; embodiment III of substructure I with embodiment A of Z1 and substructure Z2; embodiment III of substructure I with embodiment B of Z1 and substructure Z2; embodiment III of substructure I with embodiment C of Z1 and substructure Z2. FIG.1 25 Docket No.: BI-11213-PCT [0108] It is contemplated that recitations of variations for the various embodiments I, II, and III of substructure I are interchangeable with each other. Likewise, it is contemplated that recitations of variations of the various embodiments A, B, and C or Z1 and substructure Z2 are interchangeable with each other. [0109] Compounds having substructure I can also be selected from any combination of the following: SA1: 4-((5- acid [0110] FIG.1 26 Docket No.: BI-11213-PCT
SA2: 4-(((5-chl o)benzoic acid [0111] SA3: 4-[(2- - sulfanylbenzoic acid [0112] FIG.1 27 Docket No.: BI-11213-PCT
SA4: 4-[(6-bro yl]sulfanylbenzoic acid [0113] SA5: 4-((4- [0114] FIG.1 28 Docket No.: BI-11213-PCT
SA6: 4-((6-c nzoic acid [0115] SA7: 3-((5- acid [0116] FIG.1 29 Docket No.: BI-11213-PCT
SA8: 2-((5-chlo oic acid [0117] SA9: 4-((5- acid [0118] FIG.1 30 Docket No.: BI-11213-PCT
SA10: 4-((4-chlo ic acid [0119] SA11: 4-((5- acid [0120] FIG.1 31 Docket No.: BI-11213-PCT
SA12: 4-((5-chl enzoic acid [0121] SA13: 4-((5- acid [0122] FIG.1 32 Docket No.: BI-11213-PCT
SA14: 4-((5-chl [0123] SA15: 4-[ - acid [0124] FIG.1 33 Docket No.: BI-11213-PCT
-[(2-methyloxolan-2- yl)methyl]propanamide [0125] - - benzodioxin-3-ylmethyl)propanamide [0126] FIG.1 34 Docket No.: BI-11213-PCT
SA18: 3-(5-chloro-1H-indol-3-yl)-3-(4-chlorophenyl)-N-(2- methylpropyl)propanamide [0127] FIG.1 35 Docket No.: BI-11213-PCT SA19: 3-(5-chloro-1H-indol-3-yl)-3-(3-chlorophenyl)-N-(2- methylpropyl)propanamide [0128] SA20: 3-(5-chloro-1H-indol-3-yl)-3-(4-chlorophenyl)-1-morpholin-4-ylpropan-1-one No.: BI-11213-PCT
SA21: 3-(4-tert-butylphenyl)-3-(5-chloro-1H-indol-3-yl)-N-(2- methoxyethyl)propanamide [0130] FIG.1 37 Docket No.: BI-11213-PCT SA22: 1-[[2-(2-chlorophenyl)-2-(1H-indol-3-yl)ethyl]amino]-3-(4- ethoxyphenoxy)propan-2-ol;oxalic acid [0131] Additional antimicrobial compounds, which may or may not have substructure I and/or Z1 and/or substructure Z2, having activity against Staphylococcus aureus are shown in the Figures including at least FIGs. 6A-6M, 8, 10, 14, 17, 20, 29A, and 29B and further described herein. [0132] Another antimicrobial compound of the present disclosure is compound III shown below: PCT N-(3,4-dichlorophenyl)-8-[2-[(3,4-dichlorophenyl)methylamino]-2-oxoethyl]-3- hydroxy-3,4,6,6a,8,9,10,10a-octahydro-2H-pyrano[2,3-c][1,5]oxazocine-1- carboxamide [0133] Compound III has been shown to exhibit significant activity against Staphylococcus aureus. With reference to at least FIGs. 6A, 6B, 6C, 6D, and 6E, several different stereochemistries of compound III have been shown to exhibit significant activity against Staphylococcus aureus as is discussed further herein. As such, compound III and all various stereochemistries thereof are antimicrobial compounds of the present disclosure. [0134] Antimicrobial compounds of the present disclosure can also have structure IV shown below: R1 and R2 are independently selected from H, alkoxy (e.g., methoxy), halogen, or a combination thereof; when R1 or R2 is alkoxy (e.g., methoxy), the other of R1 or R2 is typically H, although not required unless specifically stated; FIG.1 39 Docket No.: BI-11213-PCT when R1 or R2 is halogen, the other of R1 or R2 is typically H, although not required unless specifically stated; and/or when R1 or R2 is halogen, the halogen is typically selected from F, Br, or Cl, and more typically is F. [0136] Compounds of structure IV have been shown to exhibit significant activity against Staphylococcus aureus. With reference to at least FIGs.6H, and 6I, compounds of different variations and stereochemistries of structure IV have been shown to exhibit significant activity against Staphylococcus aureus as is discussed further herein. As such, compounds of structure IV and all various stereochemistries thereof are antimicrobial compounds of the present disclosure. [0137] Antimicrobial compounds of the present disclosure can also have structure V shown below: [0138] Compounds of structure V allow for variation as follows: FIG.1 40 Docket No.: BI-11213-PCT R1, R2, R3, R4, and R5 are independently selected from H, halogen, or trifluoromethyl, with at least three, possibly four or all of R1, R2, R3, R4, and R5 being H, no more than two of R1, R2, R3, R4, and R5 being halogen, and/or no more than one of R1, R2, R3, R4, and R5 being trifluoromethyl. [0139] In defining compounds of structure V, the compound[s] include at least one, two, three, or any possible combination of the following: 1) R1 is halogen; 2) R5 is halogen; 3) R3 is trifluoromethyl; 4) three of R1, R2, R3, R4, and R5 are H; and/or four of R1, R2, R3, R4, and R5 are H. [0140] For each selection of halogen for structure V, the halogen is Cl, F, Br, and is typically Cl, unless otherwise indicated. [0141] Compounds of structure V has been shown to exhibit significant activity against Staphylococcus aureus. With reference to at least FIGs. 6L, and 6M, compounds of different variations of structure V have been shown to exhibit significant activity against Staphylococcus aureus as is discussed further herein. As such, compounds of structure V and all various stereochemistries thereof are antimicrobial compounds of the present disclosure. [0142] Additional antimicrobial compounds, which may or may not be stereoisomers of compound III and may or may not have structure IV and/or structure V having activity against Staphylococcus aureus are shown in the Figures, including at least FIGs. 6A- 6M. [0143] Compounds with Substructure II FIG.1 41 Docket No.: BI-11213-PCT [0144] Antimicrobial compounds that include substructure II will typically include compounds that have substructure Y1 bonded to substructure II as shown below: Substructure II O Y1 [0145] However, it is contemplated that Y1 could be bonded to substructure II at different locations. [0146] According to an embodiment A of compounds having substructure II, substructure Y1 is as follows: R12 O R10 FIG.1 11213-PCT [0147] In embodiment A of compounds that include substructure II and Y1, substructure Y1 allows for variation as follows: R6 – R10 are independently selected from H, CH3, and halogen, with no more than one of R6 – R10 being CH3, no more than three, and more typically no more than two of R6 – R10 being halogen, and at least two, and more typically at least three of R6 – R10 being H; R11 is selected from CH2, or C2-C4 alkyl or alkylene, and is typically C2H4; and R12 is selected from H, CH3, or C2-C4 alkyl or alkylene, and is typically CH3. [0148] In more specific versions of embodiment A of compounds that include substructure II, the compound includes any combination of the following: three of R6 – R10 are H; two of R6 – R10 are halogen; the halogen(s) of R6 – R10 are selected from F, Cl and Br; the halogen(s) of R6 – R10 are Cl; R11 is C2H4; and/or the halogen(s) of R6 – R10, if any, are at R8 and/or R9. [0149] According to an embodiment B of compounds that include substructure II, substructure Y1 is as follows: R10 FIG.1 Docket No.: BI-11213-PCT [0150] In embodiment B of compounds that include substructure II and substructure Y1, substructure Y1 allows for variation as follows: R6 – R10 are independently selected from H, CH3, and halogen, with no more than one of R6 – R10 being CH3, no more than three, and more typically no more than two of R6 – R10 being halogen, and at least two and more typically at least three of R6 – R10 being H; R11 is selected from CH2, or C2-C4 alkyl or alkylene and is typically CH2; and R12 is selected from H, CH3, or C2-C4 alkyl or alkylene and is typically CH3. [0151] In more specific versions of embodiment B of compounds that include substructure II, the compounds includes any combination of the following: three of R6 – R10 are H; two of R6 – R10 are halogen; the halogen(s) of R6 – R10 are selected from F, Cl and Br; the halogen(s) of R6 – R10 are Cl; and/or R11 is CH2, the halogen(s) of R6 – R10, if any, are at R7 and/or R8. [0152] In an embodiment C of compounds that include substructure II and Y1, Y1 is as follows: [0153] FIG.1 44 Docket No.: BI-11213-PCT R10 [0154] In embodiment C of compounds that include substructure II and substructure Y1, substructure Y1 allows for variation as follows: R6 – R9 are independently selected from C or N, with typically at least one, two or three of R6 – R9 being N and one or two of R6 – R9 being C; and R10 is independently selected from H, CH3, or CH2CH3 and is bonded to one of R6 – R9, which has been independently selected as N. [0155] In embodiment C of compounds that include substructure II and substructure Y1, substructure Y1 can alternatively be selected from any combination of the following: , FIG.1 BI-11213-PCT and/or N . [0156] It is contemplated that the embodiments of substructure II can be matched or combined with any of the variations of the embodiments of substructure Y1. [0157] Compounds that have been found to have activity against Neisseria gonorrhoeae and which may or may not have substructure II can also be selected from any combination of the following: FIG.1 46 Docket No.: BI-11213-PCT
. NG1: 1-((1-(2,4-dichlorophenyl)pyrrolidin-3-yl)amino)-1-oxopropan-2-yl (3,4- dichlorophenethyl)carbamate [0158] FIG.1 47 Docket No.: BI-11213-PCT
NG2: 3-(3,4- - pyrrolidin-3-yl)-2- methylpropanamide [0159] FIG.1 48 Docket No.: BI-11213-PCT
NG3: (3S)-1-(3,4-dichlorophenyl)pyrrolidin-3-amine [0160] NG4: (S)-N-(1-(3,4-dichlorophenyl)pyrrolidin-3-yl)-1-methyl-1H-pyrazole-4- carboxamide [0161] FIG.1 49 Docket No.: BI-11213-PCT
NG5: (S iazole-4- carboxamide [0162] NG6: - - 4- carboxamide [0163] FIG.1 50 Docket No.: BI-11213-PCT
NG7: amide [0164] - - [0165] FIG.1 51 Docket No.: BI-11213-PCT
N carboxamide. [0166] Antimicrobial compounds of the present disclosure can also have structure VI shown below: [0167] FIG.1 52 Docket No.: BI-11213-PCT R1 is independently selected from H, halogen (e.g., Cl), or C1-C2 alkyl (e.g., methyl); R2 is independently selected from H or halogen (e.g., Cl); R3 is independently selected from H or halogen (e.g., Cl or F); R4 is independently selected from H or C1-C2 alkyl (e.g., methyl); R5 is independently selected from H, or halogen (e.g., Cl); R6 is independently selected from H, alkoxy (e.g., methoxy) or halogen (e.g., Cl); and/or A- is an anion. [0168] In defining compounds of structure VI, the compound[s] includes at least one, two, three, or any possible combination of the following: 1) R1 is methyl or Cl; 2) R2 is Cl; 3) R3 is Cl or F; 4) R4 is methyl; 5) R5 is Cl; 6) R6 is methoxy or Cl; 7) R7 is methyl; 8) R1 is H; 9) R2 is H; 10) R3 is H; 11) R4 is H; 12) R5 is H; 13) R6 is H; and/or 14) R7 is H. [0169] In defining compounds of structure VI, the compounds may be compounds wherein R1 is H, methyl or Cl, R2 is Cl or H, R3 is Cl, F or H and R4 is H or methyl, wherein at least one of R1-R4 is not H, optionally wherein one or two of R1-R4 is not H. [0170] In defining compounds of structure VI, the compounds may be compounds wherein R5 is H or Cl and R6 is Cl or methoxy, optionally wherein R5 is H or Cl and R6 is Cl or R5 is H and R6 is methoxy. [0171] Typically, the compounds of structure VI are positively charged as indicated by the “+” sign. When included, the positive charge may be located at or adjacent either of the nitrogen atoms or may be mobile between the nitrogen atoms. These options are FIG.1 53 Docket No.: BI-11213-PCT indicated by the dashed and angled line extending between the nitrogen atoms adjacent the “+” sign. The structure VI above may be alternatively drawn with the “+” sign located at or adjacent one of the two nitrogen atoms to indicate where the positive charge is believed to be located a substantial portion or majority of the time. The positive charge can be countered or balanced by a negatively charged atom or atoms (anion[s]), which may for example be Fl-, Cl-, Br-, or OH- or another suitable anion, with the compound including the anion in solid or dissolved form. It shall be understood that, when the compound of structure VI is dissolved, the anion may dissociate from and/or help electrically balance the compound of structure VI within a liquid, gel or the like. [0172] Compounds of structure VI have been shown to exhibit significant activity against Neisseria gonorrhoeae. As such, compounds of structure VI and all various stereochemistries thereof are antimicrobial compounds of the present disclosure. [0173] Examples of compounds that have been found to have activity against Neisseria gonorrhoeae and which may or may not have structure VI can be selected from one or any combination of the following: FIG.1 54 Docket No.: BI-11213-PCT
[0174] NG10: 3-( enyl)methyl]-6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-1-ium;chloride; [0175] [0176] NG11: 3- - methyl]-6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-1-ium;chloride; [0177] FIG.1 55 Docket No.: BI-11213-PCT
[0178] NG12: 3- methyl]-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; [0179] [0180] NG13: 1-[ - -6,7- dihydro-5H-pyrrolo[1,2-a]imidazol-1-ium;chloride; [0181] FIG.1 56 Docket No.: BI-11213-PCT
[0182] NG14: 1-[( hlorophenyl)-6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-1-ium;chloride; [0183] [0184] NG15: - methyl]-6,7-dihydro- 5H-pyrrolo[1,2-a]imidazol-1-ium;chloride; and/or [0185] FIG.1 57 Docket No.: BI-11213-PCT
[0186] NG16: 1 7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride. [0187] The skilled artisan will understand that the positive charge for compounds NG10 through NG16 is shown as located at or adjacent one of the two nitrogen atoms as a convention that indicates where the positive charge is believed to be located a substantial portion or majority of the time for a selected compound. The skilled artisan will further understand that, for compounds NG10 through NG16 and other compounds of structure VI, the actual location of the positive charge, at any given time, can be at or adjacent the other nitrogen atom or mobile between the nitrogen atoms depending upon various conditions. Additionally, each of compounds NG10 through NG 16 and other compounds of structure VI could be similarly represented by replacing the core of the structure of the compound with the following: FIG.1 58 Docket No.: BI-11213-PCT , and the interpretation of the e the same but without an indication of where the positive charge is believed to be located a substantial portion or majority of the time. Within such options, the anion (A-) could be any one or a combination of the suitable anions disclosed herein. [0188] Antimicrobial compounds of the present disclosure can also have structure VII shown below: [0189] Compounds of structure VII allow for variation as follows: R1 is independently selected from H or halogen (e.g., Br); FIG.1 59 Docket No.: BI-11213-PCT R2 is independently selected from H or C1-C2 alkyl (e.g., methyl); R3 is independently selected from H or OH; R4 is independently selected from H or OH; and/or R5 is independently selected from H, OH or alkoxy (e.g., methoxy). [0190] In defining compounds of structure VII, typically at least one, more typically at least two and even possibly all three of R3-R5 is/are OH. [0191] In defining compounds of structure VII, the compound[s] include at least one, two, three, or any possible combination of the following: 1) R1 is Br; 2) R2 is methyl; 3) R3 is OH; 4) R4 is OH; 5) R5 is OH; 6) R5 is methoxy; 7) R1 is H; 8) R2 is H; 9) R3 is H; 10) R4 is H; and/or 11) R5 is H. [0192] In defining compounds of structure VI, the compounds may be compounds wherein R1 is H or Br, R2 is H or methyl, R3 is OH, R4 is H or OH and R5 is OH or methoxy. [0193] Compounds of structure VII have been shown to exhibit significant activity against Neisseria gonorrhoeae. As such, compounds of structure VII and all various stereochemistries thereof are antimicrobial compounds of the present disclosure. [0194] Examples of compounds that have been found to have activity against Neisseria gonorrhoeae and which may or may not have structure VII can also be selected from one or any combination of the following: [0195] FIG.1 60 Docket No.: BI-11213-PCT
NG19: 4-(4-p ,, l [0196] NG20: 4-[4-(2-bromophenoxy)-1H-pyrazol-5-yl]benzene-1,3-diol [0197] FIG.1 61 Docket No.: BI-11213-PCT
NG21: 5-me y y p y py yl)phenol [0198] Additional antimicrobial compounds of the present disclosure having activity against Neisseria gonorrhoeae are as follows: [0199] NG22: - [0200] FIG.1 62 Docket No.: BI-11213-PCT
NG23: N , l-2-amine [0201] [0202] Additional antimicrobial compounds of the present disclosure having activity against Neisseria gonorrhoeae are shown in the figures including at least FIGs.7A-7D, 8, 14, 17, 20, 30A, and 31C and are further described herein. [0203] It is understood that for each substructure, compound, chemical fragment and so on, all stereoisomers are included unless otherwise stated or stereochemistry is specifically indicated. [0204] In addition to being defined by their chemical structures, antimicrobial compounds of the present disclosure can be defined by their activity against (i.e., ability FIG.1 63 Docket No.: BI-11213-PCT to kill or inhibit growth) Staphylococcus aureus and/or Neisseria gonorrhoeae. Techniques for minimum inhibitory concentration (MIC) and bacterial growth are described in detail in the experimental methods section of the disclosure. Antimicrobial compounds active against Staphylococcus aureus, particularly those having substructure I but others as well, exhibit an MIC according to the described techniques of less than 32 µg/mL, 16 µg/mL, 8 µg/mL, 2 µg/mL, or 1 µg/mL. Antimicrobial compounds active against Neisseria gonorrhoeae, particularly those having substructure II but others as well, exhibit an MIC according to the described techniques of less than 64 µg/mL, 32 µg/mL, 16 µg/mL, 8 µg/mL, 5 µg/m, 2 µg/mL, or 1 µg/mL. [0205] It shall be understood that the term “compound” and/or “antimicrobial compound”, their plurals and their conjugation can be referring to any of the compounds having substructure I or substructure II or other compounds disclosed herein to have antimicrobial properties. [0206] Aspects of the instant disclosure relate to use of compounds predicted and/or tested herein to possess antimicrobial activity in pharmaceutical compositions, e.g., for treating a subject having or at risk of developing a microbial (e.g., bacterial) infection (particularly an antibiotic-resistant and/or antibiotic-tolerant bacterial infection). Advantageously, the empirically validated antimicrobials disclosed herein were initially discovered in silico, and then validated in vivo, which has greatly lowered the time and cost of the approach of the instant disclosure, as compared to preclinical screening efforts known in the art. [0207] The dissemination of antibiotic-resistance determinants threatens the stability of healthcare systems worldwide. In particular, due to the rapid emergence of antibiotic- FIG.1 64 Docket No.: BI-11213-PCT resistant bacteria, there is a growing need to discover new antibiotics. To increase the rate at which antibiotics can be discovered, a deep neural network was trained herein to be capable of predicting molecules with antibacterial activity. Model-directed predictions were performed herein upon multiple chemical libraries, and substructures and compounds having significant antimicrobial activity resulted. [0208] Altogether, the instant disclosure (1) has identified a number of molecules/compounds not previously identified as antibiotics as in fact possessing antibacterial efficacy, (2) has provided a machine learning-enhanced process for antibiotic and/or antimicrobial compound discovery (e.g., identification and/or generation), and (3) the results presented herein highlight the significant impact that machine learning is capable of exerting towards discovering new antibiotics, by, for example, increasing the true positive rate of lead compound discovery and decreasing the cost of preclinical screening. Among other useful discoveries, the instant disclosure therefore highlights the utility of deep learning approaches to expand the antibiotic arsenal through the discovery of structurally novel antibacterial molecules. [0209] Given that compounds disclosed here are well-tolerated in vivo, these compounds or analogs thereof, could represent novel structural classes of antibiotics with efficacy against antibiotic-resistant and antibiotic-susceptible bacterial pathogens or otherwise. It is expressly contemplated that compounds disclosed herein and derivatives thereof can be used against a wide range of bacterial infections. Use of such compounds with other antimicrobial agents is also expressly contemplated, optionally in an additive and/or synergistic matter. For these compounds, it is contemplated that the most probable synergistic partners are molecules that dissipate the psi component FIG.1 65 Docket No.: BI-11213-PCT of the proton motive force, since it is well known that pH dissipating molecules are synergistic with psi dissipating compounds. [0210] The development of new approaches that can substantially decrease the cost and increase the rate of antibiotic discovery is very helpful to reinfuse the world’s drug pipeline with a steady stream of candidates that show promise as next-generation therapeutics. Excitingly, the adoption of machine learning approaches is ideally suited to address these fundamental hurdles. Indeed, modern neural molecular representations have the potential to: (1) decrease the cost of lead molecule identification since high- throughput screening is limited to gathering appropriate training data, (2) increase the true positive rate of identifying compounds with the desired bioactivity, and (3) decrease the time and labor required to find these ideal compounds from months or years to weeks. [0211] In certain aspects, the present disclosure provides compositions and/or methods designed to inhibit the growth of and/or kill bacteria, particularly harmful bacteria and/or bacteria that have become or are at risk of becoming tolerant of and/or resistant to commonly administered antibiotics (e.g., amoxicillin, ampicillin, nafcillin, piperacillin, penicillin G, etc.). Tolerance specifically refers to an inability of high concentrations of antibiotics—typically lethal concentrations that are above the growth- inhibitory threshold for a given strain—to kill bacteria. Tolerance levels can be influenced by genetic mutations or induced by environmental conditions. Bacteria can often develop antibiotic tolerance and/or resistance. Resistance can tend to arise via mutations that confer increased survival, which are selected for in natural selection, and which can arise quickly in bacteria because lifespans and production of new generations FIG.1 66 Docket No.: BI-11213-PCT can be on a timescale of mere hours. Tolerant and/or resistant microbes are more difficult to treat, requiring alternative medications or higher doses of antimicrobials. These approaches may be more expensive, more toxic or both. Microbes resistant to multiple antimicrobials are called multidrug resistant (MDR). Those considered extensively drug resistant (XDR) or totally drug resistant (TDR) are sometimes called “superbugs”. [0212] An exemplary but not comprehensive list of bacteria expressly contemplated for targeting with the compositions and methods of the instant disclosure includes Achromobacter spp, Acidaminococcus fermentans, Acinetobacter calcoaceticus, Actinomyces spp, Actinomyces viscosus, Actinomyces naeslundii, Aeromonas spp, Aggregatibacter actinomycetemcomitans, Anaerobiospirillum spp, Alcaligenes faecalis, Arachnia propionica, Bacillus spp, Bacteroides spp, Bacteroides gingivalis, Bacteroides fragilis, Bacteroides intermedius, Bacteroides melaninogenicus, Bacteroides pneumosintes, Bacterionema matruchotii, Bifidobacterium spp, Buchnera aphidicola, Butyriviberio fibrosolvens, Campylobacter spp, Campylobacter coli, Campylobacter sputorum, Campylobacter upsaliensis, Capnocytophaga spp, Clostridium spp, Citrobacter freundii, Clostridium difficile, Clostridium sordellii, Corynebacterium spp, Eikenella corrodens, Enterobacter cloacae, Enterococcus spp, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Eubacterium spp, Flavobacterium spp, Fusobacterium spp, Fusobacterium nucleatum, Gordonia Bacterium spp, Haemophilus parainfluenzae, Haemophilus paraphrophilus, Lactobacillus spp, Leptotrichia buccalis, Methanobrevibacter smithii, Morganella FIG.1 67 Docket No.: BI-11213-PCT morganii, Mycobacteria spp, Mycoplasma spp, Micrococcus spp, Mycoplasma spp, Mycobacteri um chelonae, Neisseria spp, Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria cinerea, Neisseria flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria sicca, Neisseria subflava, Peptococcus spp, Peptostreptococcus spp, Plesiomonas shigelloides, Porphyromonas gingivalis, Propionibacterium spp, Propionibacterium acnes, Providencia spp, Pseudomonas aeruginosa, Ruminococcus bromii, Rothia dentocariosa, Ruminococcus spp, Sarcina spp, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus anginosus, Streptococcus mutans, Streptococcus oxalis, Streptococcus pneumoniae, Streptococcus sobrinus, Streptococcus viridans, Torulopsis glabrata, Treponema denticola, Treponema refringens, Veillonella spp, Vibrio spp, Vibrio sputorum, Wolinella succinogenes and Yersinia enterocolitica. [0213] An exemplary list of Gram-positive and/or acid-fast bacteria expressly contemplated for targeting with the compositions and methods of the instant disclosure include, without limitation, Clostridium difficile, Enterococcus (e.g., E. faecalis, E. faecium, E. casseliflavus, E. gallinarum, E. raffinosus), Mycobacterium tuberculosis, Mycobacterium avium complex (including Mycobacterium intracellulare and Mycobacterium avium), Mycobacterium smegmatis, Mycoplasms genitalium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus pyogenes, Streptococcus pneumoniae, and Mycobaterium leprae. FIG.1 68 Docket No.: BI-11213-PCT [0214] An exemplary list of Gram-negative bacteria expressly contemplated for targeting with the compositions and methods of the instant disclosure include, without limitation, Acinetobacter spp. (including Acinetobacter baumannii), Campylobacter, Neisseria spp. (including Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria cinerea, Neisseria flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria sicca, Neisseria subflava), Providencia spp., Enterobacter spp. (including Enterobacter cloacae and Enterobacter aerogenes), Klebsiella spp. (including Klebsiella pneumoniae), Salmonella, Pasteurella spp., Proteus spp. (including Proteus mirabilis), Serratia spp. (including Serratia marcescens), Citrobacter spp., Escherichia spp. (including Escherichia coli), Acinetobacter, Morganella morganii, Pseudomonas aeruginosa, Burkholderia pseudomallei, Burkholderia cenocepacia, Helicobacter pylori, Treponema pallidum and Hemophilus influenza. (See, e.g., Cohen et al. Cell Host & Microbe 13: 632-642, the contents of which are incorporated by reference herein in their entirety.) [0215] The instant disclosure expressly contemplates targeting of any of (or any combination of) the above-listed forms of Gram-positive and/or Gram-negative bacteria, particularly those forms of the above-recited bacteria that possess or are at risk of developing tolerance and/or resistance to antibiotics previously known in the art. [0216] According to aspects of the present disclosure, a composition and/or formulation of the instant disclosure can be administered to a subject to treat mixed infections that comprise different types of Gram-negative bacteria, different types of Gram-positive bacteria, or which comprise both Gram-positive and Gram-negative bacteria. These FIG.1 69 Docket No.: BI-11213-PCT types of infections include, without limitation, intra-abdominal infections, and obstetrical/gynecological infections. [0217] A host of alternative or additional pathogens are described herein and it is specifically contemplated that these pathogens can be the cause of an infection that the compounds and/or pharmaceutical compositions of the present disclosure can be used to treat or prevent. [0218] Algae [0219] Chlamydomonas is a genus of green algae consisting of about 325 species, all unicellular flagellates, found in stagnant water, damp soil, freshwater, seawater, and snow. Chlamydomonas is used as a model organism for molecular biology, especially studies of flagellar motility and chloroplast dynamics, biogeneses, and genetics. Chlamydomonas contain ion channels that are directly activated by light. The Chlamydomonas genus includes, but is not limited to, the strain Chlamydomonas reinhardtii. Chlamydomonas reinhardtii is an especially well studied biological model organism, partly due to its ease of culturing and the ability to manipulate its genetics (e.g., Chlamydomonas reinhardtii CC-503 auto-fluorescent strain). [0220] Yeast [0221] Yeasts are unicellular organisms belonging to one of three classes: Ascomycetes, Basidiomycetes and fungi imperfecta. Pathogenic yeast strains, including mutants thereof, are expressly contemplated for use and/or targeting in the instant disclosure. Explicitly contemplated yeast strains include Saccharomyces, Candida, Cryptococcus, Hansenula, Kluyveromyces, Pichia, Rhodotorula, Schizosaccharomyces and Yarrowia. Exemplary species include Saccharomyces cerevisiae, Saccharomyces pastorianus, FIG.1 70 Docket No.: BI-11213-PCT Candida albicans, Candida tropicalis, Candida stellatoidea, Candida glabrata, Candida krusei, Candida parapsilosis, Candida guilliermondii, Candida viswanathii, Candida lusitaniae, Candida kefyr, Candida laurentii, Cryptococcus neoformans, Hansenula anomala, Hansenula polymorpha, Kluyveromyces fragilis, Kluyveromyces lactis, Kluyveromyces marxianus var. Lactis, Pichia pastoris, Rhodotorula rubra, Schizosaccharomyces pombe, Leucosporidium frigidum, Saccharomyces telluris, Candida slooffi, Torulopsis, Trichosporon cutaneum, Dekkera intermedia, Candida blankii, Cryptococcus gattii, Rhodotorula mucilaginosa, Brettanomyces bruxellensis, Candida stellata, Torulaspora delbrueckii, Zygosaccharomyces bailii, Brettanomyces anomalus, Brettanomyces custersianus, Brettanomyces naardenensis, Brettanomyces nanus, Dekkera bruxellensis, Dekkera anomala and Yarrowia lipolytica. As will be understood to one of ordinary skill in the art, a number of these species include a variety of subspecies, types and subtypes, etc. that are to be understood as included within the aforementioned species. [0222] Other Microbes [0223] Other expressly contemplated microbes include, without limitation, Aspergillus, Blastomyces, Coccidioides, C. neoformans, C. gattii, Histoplasma, Mucormycetes, Mycetoma, Pneumocytsis jirovencii, Trichophyton, Microsporum, Epidermophyton, Sporothrix, Paracoccidioidomycosis, Talaromycosis, and Cryptococcus. [0224] Methods of Treatment [0225] The compositions and methods of the present disclosure may be used in the context of several therapeutic or prophylactic applications. Compositions of the instant FIG.1 71 Docket No.: BI-11213-PCT disclosure can be selected and/or administered as a single agent, or to augment the efficacy of another therapy (second therapy); it may be desirable to combine these compositions and methods with one another, or with other agents and methods effective in the treatment, amelioration, or prevention of infections and/or diseases. [0226] In certain embodiments of the instant disclosure, one or more antimicrobial compounds can be administered to a subject. It is contemplated that in certain embodiments, one or more antimicrobial compounds of the instant disclosure can be co-administered and/or administration of one antimicrobial compound of the instant disclosure can precede or follow administration of a second antimicrobial agent. It is also expressly contemplated that the antimicrobial agent compositions and methods of the instant disclosure can optionally be administered in further combination with other agents, including, e.g., other agents capable of enhancing antimicrobial agent efficacy (such as, e.g., β-lactamase inhibitors, among other antibiotic potentiators/adjuvants that are known in the art). [0227] Administration of a composition of the present disclosure to a subject will follow general protocols for the administration described herein, and the general protocols for the administration of a particular secondary therapy will also be followed, considering the toxicity, if any, of the treatment. It is expected that the treatment cycles would be repeated as necessary. It also is contemplated that various standard therapies may be applied in combination with the described therapies. [0228] Pharmaceutical Compositions FIG.1 72 Docket No.: BI-11213-PCT [0229] Compounds of the present disclosure can be incorporated into a variety of formulations for therapeutic use (e.g., by administration) or in the manufacture of a medicament (e.g., for treating or preventing a bacterial infection) by combining the agents with appropriate pharmaceutically acceptable carriers (e.g., diluents, anti- oxidants, preservatives, etc.) and may be formulated into preparations in solid, semi- solid, liquid or gaseous forms. Examples of such formulations include, without limitation, tablets, capsules, powders, granules, ointments, solutions, suppositories, suspensions, emulsions, injections, inhalants, gels, microspheres, and aerosols. [0230] Pharmaceutical compositions can include, depending on the formulation desired, pharmaceutically-acceptable, non-toxic carriers, which are vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. Examples of such carriers/diluents include, without limitation, distilled water, buffered water, physiological saline, PBS, Ringer's solution, dextrose solution, and Hank's solution. A pharmaceutical composition or formulation of the present disclosure can further include other carriers, adjuvants, or non-toxic, nontherapeutic, nonimmunogenic stabilizers, excipients and the like. The compositions can also include additional substances to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, wetting agents and detergents. [0231] Further examples of formulations that are suitable for various types of administration can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, Pa., 17th ed. (1985). For a brief review of methods for drug delivery, see, Langer, Science 249: 1527-1533 (1990). FIG.1 73 Docket No.: BI-11213-PCT [0232] For oral administration, the active ingredient can be administered in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. The active component(s) can be encapsulated in gelatin capsules together with inactive ingredients and powdered carriers, such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talcum, magnesium carbonate. Examples of additional inactive ingredients that may be added to provide desirable color, taste, stability, buffering capacity, dispersion or other known desirable features are red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, and edible white ink. [0233] Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. [0234] Formulations suitable for parenteral administration include aqueous and non- aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. [0235] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with FIG.1 74 Docket No.: BI-11213-PCT the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences 66 (1977):1- 19, incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds to be administered carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, FIG.1 75 Docket No.: BI-11213-PCT nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [0236] Additionally, as used herein, the term “pharmaceutically acceptable ester” refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound (e.g., an FDA-approved compound where administered to a human subject) or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moeity advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. [0237] Furthermore, the term “pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of certain compounds of the present application which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the FIG.1 76 Docket No.: BI-11213-PCT application. The term “prodrug” refers to compounds that are rapidly transformed in vivo to yield the parent compound of an agent of the instant disclosure, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro- drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, (1987), both of which are incorporated herein by reference. [0238] The components used to formulate the pharmaceutical compositions are preferably of high purity and are substantially free of potentially harmful contaminants (e.g., at least National Food (NF) grade, generally at least analytical grade, and more typically at least pharmaceutical grade). Moreover, compositions intended for in vivo use are usually sterile. To the extent that a given compound must be synthesized prior to use, the resulting product is typically substantially free of any potentially toxic agents, particularly any endotoxins, which may be present during the synthesis or purification process. Compositions for parental administration are also sterile, substantially isotonic and made under GMP conditions. [0239] Formulations may be optimized for retention and stabilization in a subject and/or tissue of a subject, e.g., to prevent rapid clearance of a formulation by the subject. Stabilization techniques include cross-linking, multimerizing, or linking to groups such as polyethylene glycol, polyacrylamide, neutral protein carriers, etc. in order to achieve an increase in molecular weight. [0240] Other strategies for increasing retention include the entrapment of the agent, such as an antibiotic compound, in a biodegradable or bioerodible implant. The rate of release FIG.1 77 Docket No.: BI-11213-PCT of the therapeutically active agent is controlled by the rate of transport through the polymeric matrix, and the biodegradation of the implant. The transport of drug through the polymer barrier will also be affected by compound solubility, polymer hydrophilicity, extent of polymer cross-linking, expansion of the polymer upon water absorption so as to make the polymer barrier more permeable to the drug, geometry of the implant, and the like. The implants are of dimensions commensurate with the size and shape of the region selected as the site of implantation. Implants may be particles, sheets, patches, plaques, fibers, microcapsules and the like and may be of any size or shape compatible with the selected site of insertion. [0241] The implants may be monolithic, i.e. having the active agent homogenously distributed through the polymeric matrix, or encapsulated, where a reservoir of active agent is encapsulated by the polymeric matrix. The selection of the polymeric composition to be employed will vary with the site of administration, the desired period of treatment, patient tolerance, the nature of the disease/infection to be treated and the like. Characteristics of the polymers will include biodegradability at the site of implantation, compatibility with the agent of interest, ease of encapsulation, and a half- life in the physiological environment. [0242] Biodegradable polymeric compositions which may be employed may be organic esters or ethers, which when degraded result in physiologically acceptable degradation products, including the monomers. Anhydrides, amides, orthoesters or the like, by themselves or in combination with other monomers, may find use. The polymers will be condensation polymers. The polymers may be cross-linked or non-cross-linked. Of particular interest are polymers of hydroxyaliphatic carboxylic acids, either homo- or FIG.1 78 Docket No.: BI-11213-PCT copolymers, and polysaccharides. Included among the polyesters of interest are polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, polycaprolactone, and combinations thereof. By employing the L-lactate or D-lactate, a slowly biodegrading polymer is achieved, while degradation is substantially enhanced with the racemate. Copolymers of glycolic and lactic acid are of particular interest, where the rate of biodegradation is controlled by the ratio of glycolic to lactic acid. The most rapidly degraded copolymer has roughly equal amounts of glycolic and lactic acid, where either homopolymer is more resistant to degradation. The ratio of glycolic acid to lactic acid will also affect the brittleness of in the implant, where a more flexible implant is desirable for larger geometries. Among the polysaccharides of interest are calcium alginate, and functionalized celluloses, particularly carboxymethylcellulose esters characterized by being water insoluble, a molecular weight of about 5 kD to 500 kD, etc. Biodegradable hydrogels may also be employed in the implants of the individual instant disclosure. Hydrogels are typically a copolymer material, characterized by the ability to imbibe a liquid. Exemplary biodegradable hydrogels which may be employed are described in Heller in: Hydrogels in Medicine and Pharmacy, N. A. Peppes ed., Vol. III, CRC Press, Boca Raton, Fla., 1987, pp 137-149. [0243] Pharmaceutical Dosages [0244] Pharmaceutical compositions of the present disclosure containing an antibacterial compound described herein may be used (e.g., administered to an individual, such as a human individual, in need of treatment with an antibiotic) in accord with known methods, such as oral administration, intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, FIG.1 79 Docket No.: BI-11213-PCT intracerebrospinal, intracranial, intraspinal, subcutaneous, intraarticular, intrasynovial, intrathecal, topical, or inhalation routes. [0245] Dosages and desired drug concentration of pharmaceutical compositions of the present disclosure may vary depending on the particular use envisioned and the pharmaceutically acceptable concentration of compound determined. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary artisan. Animal experiments provide reliable guidance for the determination of effective doses for human therapy. Interspecies scaling of effective doses can be performed following the principles described in Mordenti, J. and Chappell, W. “The Use of Interspecies Scaling in Toxicokinetics,” In Toxicokinetics and New Drug Development, Yacobi et al., Eds, Pergamon Press, New York 1989, pp.42-46. [0246] For in vivo administration of any of the compounds of the present disclosure, normal dosage amounts may vary from about 10 ng/kg up to about 100 mg/kg of an individual's and/or subject's body weight or more per day, depending upon the route of administration. In some embodiments, the dose amount is about 1 mg/kg/day to 10 mg/kg/day. For repeated administrations over several days or longer, depending on the severity of the disease, disorder, or condition to be treated, the treatment is sustained until a desired suppression of symptoms is achieved. [0247] An effective amount of an antimicrobial compound of the instant disclosure may vary, e.g., from about 0.001 mg/kg to about 1000 mg/kg or more in one or more dose administrations for one or several days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg FIG.1 80 Docket No.: BI-11213-PCT to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg. [0248] An exemplary dosing regimen may include administering an initial dose of an antimicrobial compound of the disclosure of about 200 μg/kg, followed by a weekly maintenance dose of about 100 μg/kg every other week. Other dosage regimens may be useful, depending on the pattern of pharmacokinetic decay that the physician wishes to achieve. For example, dosing an individual from one to twenty-one times a week is contemplated herein. In certain embodiments, dosing ranging from about 3 μg/kg to about 2 mg/kg (such as about 3 μg/kg, about 10 μg/kg, about 30 μg/kg, about 100 μg/kg, about 300 μg/kg, about 1 mg/kg, or about 2 mg/kg) may be used. In certain embodiments, dosing frequency is three times per day, twice per day, once per day, once every other day, once weekly, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, or once monthly, once every two months, once every three months, or longer. Progress of the therapy is easily monitored by conventional techniques and assays. The dosing regimen, including the antimicrobial compound administered, can vary over time independently of the dose used. [0249] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the antimicrobial compound (also described herein as the active ingredient) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit. FIG.1 81 Docket No.: BI-11213-PCT [0250] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. [0251] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.001% and 100% (w/w) and more typically between 0.1% and 50% (w/w) active ingredient. [0252] It is generally contemplated that most any of the pharmaceutical excipients disclosed herein can be a part of the whole of an acceptable pharmaceutically acceptable carrier of the present disclosure. It is also contemplated that most any of the pharmaceutical excipients disclosed herein can be considered as separate from the pharmaceutically acceptable carrier of the present disclosure, but still part of the pharmaceutical compositions disclosed herein. [0253] Pharmaceutically acceptable excipients/carriers used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. FIG.1 82 Docket No.: BI-11213-PCT Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition. [0254] Exemplary diluents/carriers include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof. [0255] Exemplary granulating and/or dispersing agents/carriers include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl- pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof. [0256] Exemplary surface active agents/emulsifiers/carriers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol FIG.1 83 Docket No.: BI-11213-PCT distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, Poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof. [0257] Exemplary binding agents/carriers include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, FIG.1 84 Docket No.: BI-11213-PCT cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof. [0258] Further exemplary preservatives/excipients/carriers include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent. [0259] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. [0260] Exemplary chelating agents/carriers include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, FIG.1 85 Docket No.: BI-11213-PCT imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. [0261] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. [0262] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. [0263] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. [0264] Other excipients/preservatives/carriers include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®. [0265] Still other excipients/carriers include buffering agents, lubricating agents and oils. [0266] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium FIG.1 86 Docket No.: BI-11213-PCT levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof. [0267] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof. [0268] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, FIG.1 87 Docket No.: BI-11213-PCT diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof. [0269] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof. [0270] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally FIG.1 88 Docket No.: BI-11213-PCT employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [0271] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [0272] To prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle. [0273] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient. [0274] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, FIG.1 89 Docket No.: BI-11213-PCT glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent. [0275] Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. FIG.1 90 Docket No.: BI-11213-PCT [0276] The active ingredient (i.e., antimicrobial compound) can be in a micro- encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes. [0277] Dosage forms for topical and/or transdermal administration of an active ingredient described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively, or additionally, the rate can be FIG.1 91 Docket No.: BI-11213-PCT controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel. [0278] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively, or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable. [0279] Formulations suitable for topical administration (e.g., ophthalmic administration) include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 0.01% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein. [0280] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient FIG.1 92 Docket No.: BI-11213-PCT and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self- propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form. [0281] Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally, the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient). [0282] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the FIG.1 93 Docket No.: BI-11213-PCT active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers. [0283] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares. [0284] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, FIG.1 94 Docket No.: BI-11213-PCT when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein. [0285] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure. [0286] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions that are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. [0287] Drugs (e.g., antimicrobial compounds) provided herein can be formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the agents described herein will be FIG.1 95 Docket No.: BI-11213-PCT decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts. [0288] The active agents and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the agent or pharmaceutical composition described herein is suitable for oral delivery or intravenous injection to a subject. FIG.1 96 Docket No.: BI-11213-PCT [0289] The exact amount of an active ingredient/antimicrobial compound required to achieve a pharmaceutically effective amount may vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder/infection, identity of the particular agent, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of an agent (e.g., an antibiotic) described herein. [0290] As noted elsewhere herein, a drug (e.g., an antimicrobial compound) of the instant disclosure may be administered via a number of routes of administration, including but not limited to: subcutaneous, intravenous, intrathecal, intramuscular, intranasal, oral, transepidermal, parenteral, by inhalation, or intracerebroventricular. [0291] The term “injection” or “injectable” as used herein refers to a bolus injection (administration of a discrete amount of an agent for raising its concentration in a bodily fluid), slow bolus injection over several minutes, or prolonged infusion, or several consecutive injections/infusions that are given at spaced apart intervals. In some embodiments of the present disclosure, a formulation as herein defined is administered to the subject by bolus administration. [0292] A drug (e.g., an antimicrobial compound) or other therapy of the instant disclosure is administered to the subject in an amount sufficient to achieve a desired effect at a desired site (e.g., reduction of bacterial infection, bacterial abundance, symptoms, etc.) determined by a skilled clinician to be effective. In some embodiments FIG.1 97 Docket No.: BI-11213-PCT of the disclosure, the antimicrobial compound is administered at least once a year. In other embodiments of the disclosure, the antimicrobial compound is administered at least once a day. In other embodiments of the disclosure, the antimicrobial compound is administered at least once a week. In some embodiments of the disclosure, the antimicrobial compound is administered at least once a month. [0293] Additional exemplary doses for administration of a compound or pharmaceutical composition of the disclosure to a subject include, but are not limited to, the following: 1-20 mg/kg/day, 2-15 mg/kg/day, 5-12 mg/kg/day, 10 mg/kg/day, 1-500 mg/kg/day, 2- 250 mg/kg/day, 5-150 mg/kg/day, 20-125 mg/kg/day, 50-120 mg/kg/day, 100 mg/kg/day, at least 10 μg/kg/day, at least 100 μg/kg/day, at least 250 μg/kg/day, at least 500 μg/kg/day, at least 1 mg/kg/day, at least 2 mg/kg/day, at least 5 mg/kg/day, at least 10 mg/kg/day, at least 20 mg/kg/day, at least 50 mg/kg/day, at least 75 mg/kg/day, at least 100 mg/kg/day, at least 200 mg/kg/day, at least 500 mg/kg/day, at least 1 g/kg/day, and a therapeutically effective dose that is less than 500 mg/kg/day, less than 200 mg/kg/day, less than 100 mg/kg/day, less than 50 mg/kg/day, less than 20 mg/kg/day, less than 10 mg/kg/day, less than 5 mg/kg/day, less than 2 mg/kg/day, less than 1 mg/kg/day, and less than 500 μg/kg/day. [0294] In certain embodiments, when multiple doses are administered to a subject or applied to a tissue, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject FIG.1 98 Docket No.: BI-11213-PCT or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of an agent (e.g., an antibiotic) described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of an agent (e.g., an antimicrobial compound) described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of an agent (e.g., an antimicrobial FIG.1 99 Docket No.: BI-11213-PCT compound) described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of an agent (e.g., an antimicrobial compound) described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of an agent (e.g., an antimicrobial compound) described herein. [0295] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. In certain embodiments, a dose described herein is a dose to an adult human whose body weight is 70 kg. [0296] It will be also appreciated that an agent (e.g., an antimicrobial compound) or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents), which are different from the agent or composition and may be useful as, e.g., combination therapies. [0297] The antimicrobial compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease or infection (e.g., an antibiotic tolerant or resistant bacterial infection) in a subject in need thereof, in preventing a disease or infection in a subject in need thereof, in reducing the risk of developing a disease or infection in a subject in need thereof, etc. in a subject or tissue. In certain embodiments, a pharmaceutical composition described herein including an FIG.1 100 Docket No.: BI-11213-PCT agent (e.g., an antibiotic compound) described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the agent and the additional pharmaceutical agent, but not both. [0298] In some embodiments of the disclosure, a therapeutic agent distinct from a first therapeutic agent (i.e., the antimicrobial compound) of the disclosure is administered prior to, in combination with, at the same time, or after administration of the agent of the disclosure. In some embodiments, the second therapeutic agent is selected from the group consisting of a chemotherapeutic, an immunotherapy, an antioxidant, an anti- inflammatory agent, an antimicrobial, a steroid, etc. [0299] The antimicrobial compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease or infection described herein. Each additional FIG.1 101 Docket No.: BI-11213-PCT pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the agent or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the agent described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. [0300] The additional pharmaceutical agents include, but are not limited to, additional antibiotics, antimicrobials, anti-proliferative agents, cytotoxic agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti- allergic agents, contraceptive agents, and pain-relieving agents. [0301] Dosages for a particular agent of the instant disclosure may be determined empirically in individuals who have been given one or more administrations of the agent. [0302] Administration of an agent/compound of the present disclosure can be continuous or intermittent, depending, for example, on the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners. The administration of an agent may be FIG.1 102 Docket No.: BI-11213-PCT essentially continuous over a preselected period of time or may be in a series of spaced doses. [0303] Guidance regarding particular dosages and methods of delivery is provided in the literature; see, for example, U.S. Pat. Nos.4,657,760; 5,206,344; or 5,225,212. It is within the scope of the instant disclosure that different formulations will be effective for different treatments and different disorders, and that administration intended to treat a specific organ or tissue may necessitate delivery in a manner different from that to another organ or tissue. Moreover, dosages may be administered by one or more separate administrations, or by continuous infusion. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays. [0304] Kits [0305] The instant disclosure also provides kits containing agents of this disclosure for use in the methods of the present disclosure. Kits of the instant disclosure may include one or more containers comprising an agent (e.g., an antibiotic) and/or composition of this disclosure. In some embodiments, the kits further include instructions for use in accordance with the methods of this disclosure. In some embodiments, these instructions comprise a description of administration of the agent to treat or prevent, e.g., an infection and/or disease. In some embodiments, the instructions comprise a description of how to administer an antibiotic to a bacterial population, and/or to a subject infected or suspected to be infected or at risk of infection with a bacteria. FIG.1 103 Docket No.: BI-11213-PCT [0306] The instructions generally include information as to dosage, dosing schedule, and route of administration for the intended use/treatment. Instructions supplied in the kits of the instant disclosure are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable. Instructions may be provided for practicing any of the methods described herein. The kits of this disclosure are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar® or plastic bags), and the like. The container may further comprise a pharmaceutically active agent. [0307] Kits may optionally provide additional components such as buffers and interpretive information. Normally, the kit comprises a container and a label or package insert(s) on or associated with the container. [0308] The practice of the present disclosure employs, unless otherwise indicated, conventional techniques of chemistry, molecular biology, microbiology, recombinant DNA, genetics, immunology, cell biology, cell culture and transgenic biology, which are within the skill of the art. See, e.g., Maniatis et al., 1982, Molecular Cloning (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.); Sambrook et al., 1989, Molecular Cloning, 2nd Ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.); Sambrook and Russell, 2001, Molecular Cloning, 3rd Ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.); Ausubel et al., 1992), Current Protocols in Molecular Biology (John Wiley & Sons, including periodic updates); Glover, 1985, DNA Cloning (IRL Press, Oxford); Anand, 1992; Guthrie and Fink, 1991; Harlow and Lane, 1988, Antibodies, (Cold Spring Harbor Laboratory Press, Cold FIG.1 104 Docket No.: BI-11213-PCT Spring Harbor, N.Y.); Jakoby and Pastan, 1979; Nucleic Acid Hybridization (B. D. Hames & S. J. Higgins eds.1984); Transcription And Translation (B. D. Hames & S. J. Higgins eds.1984); Culture Of Animal Cells (R. I. Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells And Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide To Molecular Cloning (1984); the treatise, Methods In Enzymology (Academic Press, Inc., N.Y.); Gene Transfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods In Enzymology, Vols. 154 and 155 (Wu et al. eds.), Immunochemical Methods In Cell And Molecular Biology (Mayer and Walker, eds., Academic Press, London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D. M. Weir and C. C. Blackwell, eds., 1986); Riott, Essential Immunology, 6th Edition, Blackwell Scientific Publications, Oxford, 1988; Hogan et al., Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986); Westerfield, M., The zebrafish book. A guide for the laboratory use of zebrafish (Danio rerio), (4th Ed., Univ. of Oregon Press, Eugene, 2000). [0309] Compound Identification and/or Creation [0310] FIG.1A is an illustration of an environment 100 in an example implementation that is operable for antimicrobial identification and/or creation as described herein. The illustrated environment 100 includes a service provider system 102, a computing device 104, a data supply 106, and a data processor 108 that are communicatively coupled, one to another directly or via a network 110. Although functionality of the data processor 108 is illustrated as separate from the service provider system 102, the computing device 104, and the data supply 106, this functionality may be incorporated as part of FIG.1 105 Docket No.: BI-11213-PCT the service provider system 102, the computing device 104, and/or the data supply 106, further divided among other entities, and so forth. By way of example, an entirety of or portions of the functionality of the sequencing data processor 108 may be incorporated as part of the data supply 106, the computing device 104, or both. It will also be understood that the service provider system 102, the computing device 104, the data supply 106, the data processor 108, and the network 110 can be a single entity or multiple entities that combine to function as the respective component. For example, and without limitation, the data processor 108 can be a single processor or multiple processors that combine together to provide the functionality of the data processor 108. As another example, the computing device 104 can be a single computing device 104 (e.g., computer) or multiple computing devices (e.g., computers) connected together as a network. [0311] Computing devices that are usable as the computing device 104 to implement the service provider system 102 and the data processor 108 may be configured in a variety of ways. A computing device, for instance, may be configured as a desktop computer, a laptop computer, a mobile device (e.g., assuming a handheld configuration such as a tablet or mobile phone), and so forth. Thus, the computing device may range from full resource devices with substantial memory and processor resources (e.g., personal computers, game consoles) to a low-resource device with limited memory and/or processing resources (e.g., mobile devices). Additionally, a computing device may be representative of a plurality of different devices, such as multiple servers utilized to perform operations “over the cloud,” as further described in relation to FIG.32. FIG.1 106 Docket No.: BI-11213-PCT [0312] The service provider system 102 is illustrated as including an application manager module 112 that is representative of functionality to provide access to the data processor 108 to a user of the computing device 104 via the network 110. The application manager module 112, for instance, may expose content or functionality of the data processor 108 that is accessible via the network 110 by an application 114 of the computing device 104. The application 114 may be configured as a network- enabled application, a browser, a native application, and so on, that exchanges data with the service provider system 102 via the network 110. The data can be employed by the application 114 to enable the user of the computing device 104 to communicate with the service provider system 102, such as to receive application updates and features when the service provider system 102 provides functionality to manage the application 114. [0313] In the context of the described techniques, the application 114 includes functionality to input parameters for aiding in identifying and/or creating compounds as well as to analyze data generated by steps used to identify and/or create compounds. In the illustrated example, the application 114 includes an interface 116 that is implemented at least partially in hardware of the computing device 104 for facilitating communication between the computing device 104 and the data processor 108. By way of example, the interface 116 includes functionality to receive inputs to the data processor 108 from the computing device 104 (e.g., from a user of the computing device 104) and output information, data, and so forth from the data processor 108 to the computing device 104, as will be further elaborated herein. FIG.1 107 Docket No.: BI-11213-PCT [0314] The environment 100 includes a screening module (e.g., a substructure screening module) 120, which is usable to screen a library of initial chemical substructures. The screening module 120 is usable to predict antimicrobial activity of the chemical substructures, however, the screening module 120 may also be used to predict other properties of the substructures as further described herein. [0315] FIG. 1B is a flowchart of an example of process 150 usable to identify and/or create compounds having antimicrobial activity. At 152, a library of chemical substructures is screened, for example by the screening module 120, to predict properties of the chemical substructures within the library. [0316] As suggested, a library of initial chemical substructures is screened, for example at 152 by the screening module 120, to predict the activity of the initial chemical substructures against a target microbe or target microbes. The screening involves training an antimicrobial predictive machine learning (APML) module 126, to identify which of the chemical substructures has greater potential to exhibit antimicrobial activity against the target microbe(s). Thereafter, the library of initial chemical substructures is provided to the antimicrobial predictive machine learning module 126 to identify which of the initial chemical substructures has greater potential to exhibit antimicrobial activity against the target microbe(s). [0317] As an example, the antimicrobial predictive machine learning module 126 can include one or more (e.g., at least 5, 10, 15 or more) graph neural networks (GNNs). Such an antimicrobial predictive machine learning module 126 is typically a deep learning model that infers molecular properties by representing a chemical structure as a mathematical graph. Using “message passing” operations, the nodes or edges of the FIG.1 108 Docket No.: BI-11213-PCT mathematical graph are assigned values that are iteratively updated in a way that depends on the training. For a given chemical structure or substructure, the machine learning module can produce predictive results in a variety of formats. As one example, the antimicrobial predictive machine learning module 126 is usable to produce a single output value between 0 and 1 for each chemical structure or substructure, representing the probability that the structure of substructure possesses a specific property of interest (e.g., antibacterial activity or cytotoxicity). For example, the antimicrobial predictive machine learning module 126 is usable as to predict the probability that a chemical structure or chemical substructure will exhibit antimicrobial activity against a target microbe. [0318] For identifying and creating the particular antimicrobial compounds disclosed herein, the machine learning module was trained to predict the antibacterial activity of chemical structures and/or chemical substructures against at least S. aureus or N. gonorrhoeae. Ensembles of 20 GNN models were trained using a model referred to herein as Chemprop, which is further described herein. The exemplary machine learning module was trained on empirical, binarized growth inhibition data for 39,312 compounds (S. aureus RN4220) or 38,765 compounds (N. gonorrhoeae ATCC 49226). [0319] In addition to predicting antimicrobial activity, the screening of the chemical substructures 152 can also include screening for properties other than antimicrobial activity. The chemical substructures can additionally or alternatively be screened, for example by a toxicity predictive machine learning (TPML) module 128, to predict if the substructures are likely to exhibit toxicity to mammals (e.g., humans). Like the APML module 126, the TPML module 128 can be trained using compounds with FIG.1 109 Docket No.: BI-11213-PCT known cytotoxicity and compounds without cytotoxicity. In fact, the TPML module 128 can be the same as or similar to the APML module 126 but trained on a different set of data. [0320] To avoid selecting cytotoxic compounds for the particular compounds disclosed herein, models were leveraged to predict cytotoxicity against human primary skeletal muscle (HSkM) hepatocarcinoma (HepG2), and lung fibroblast (IMR-90) cells. These models have been benchmarked; here, they were validated for both chemical substructures and compounds, as discussed further herein. Two ensembles of Chemprop models were employed to predict antibacterial activity and three ensembles of Chemprop models were employed to predict human cell cytotoxicity. [0321] With reference to the table in FIG. 2A, performance metrics of deep learning models are presented relative to training of the machine learning module. Each metric is detailed; for the S. aureus growth inhibition, HSkMC cytotoxicity, HepG2 cytotoxicity, and IMR-90 cytotoxicity models, benchmarking was performed using 10 models and an 80-20 split of the data. Error intervals indicate the variation in AUPRC generated from bootstrapping. For the N. gonorrhoeae growth inhibition model, benchmarking was performed using five-fold cross-validation, and standard error (SE) indicates the standard deviation across the five folds. [0322] Once trained, the screening module 120, particularly the machine learning modules, are employed to screen the library of initial chemical substructures to identify which of the initial chemical substructures has greater potential to exhibit antimicrobial activity against the target microbe(s) and can be considered active chemical substructures. The library of initial chemical substructures typically includes at least FIG.1 110 Docket No.: BI-11213-PCT 100,000 but not greater than 10 billion substructures. The substructures are provided to the machine learning module(s) such that the module(s) determines a likelihood that each of the substructures will provide the desired property (e.g., antimicrobial activity, lack of toxicity, and so on). [0323] The library of initial chemical substructures can be created and/or attained according to a variety of protocols. Many libraries of chemical substructures already exist and can be screened as discussed herein. The library can also include substructures that are generated. According to one protocol, a set of atoms such as C, N, O, F, Cl, Br, S, or any combination thereof can be identified and used to create all or a subset of chemically possible and/or stable substructures having a preselected number (e.g., at least 8, 9, 10 or more, but no greater than 25, 19, 18 or less) of such atoms. [0324] For identifying and creating the antimicrobial compounds disclosed herein a library of ~106 million chemical substructures that largely followed geometrical shear stress and functional group stability criteria to retain chemically meaningful structures (“possible substructures”) was screened. The library combined five large sub-libraries: (1) all possible substructures containing up to 11 atoms of C, N, O, and F (26,434,571 substructures); (2) all additional possible substructures having up-to-11 atom fragments of C, N, O, Cl, and S (1,089,000 substructures); (3) a random subsample of possible up- to-17 atom substructures of C, N, O, S, and halogen atoms (50,000,000 fragments); (4) all possible up-to-17 atom substructures of C, N, O, S, and halogen atoms covering a broad range of molecular weights, polarity and stereochemical complexity (10,351,204 substructures); and (5) all substructures in Enamine’s Readily AccessibLe (REAL) FIG.1 111 Docket No.: BI-11213-PCT database that have improved synthetic accessibility and can vary in the number of atoms 36–40 (18,338,026 substructures). [0325] The structural novelty of these initial chemical substructures was examined by visualizing the chemical space they occupied, relative to known antibiotics, using t- distributed stochastic neighborhood embedding based on the Tanimoto similarity as a distance metric (See FIG. 2B). This two-dimensional projection of chemical space where structurally similar fragments (i.e., substructures) or compounds are closer in distance and vice-versa, showed that the assembled substructures substantively expand on the chemical diversity beyond that found in a manually compiled set of 559 antibacterial compounds. Overall, the library of initial chemical substructures included 106,212,801 substructures, which were screened for selective antibacterial activity using the machine learning module. [0326] For particular compounds of the present disclosure, the library of initial substructures was provided to the machine learning module to predict the likelihood of the initial substructures exhibiting antimicrobial activity. The library was screened to predict antibacterial activity against S. aureus and those substructures with prediction scores > 0.05 in the GDB and FDB databases and, due to better synthetic accessibility, > 0.1 in Enamine’s REAL Fragment database were shortlisted as active. A similar analysis was run with the same prediction score thresholds for modules predicting antibacterial activity against N. gonorrhoeae, but for a subset of 45,858,026 substructures in the library that were expected to be highly accessible for synthesis. This resulted in 1,410,490 substructures (1.3%) predicted to be active against S. aureus FIG.1 112 Docket No.: BI-11213-PCT and 3,844,505 fragments (8.4%) predicted to be active against N. gonorrhoeae (see FIG. 3). [0327] As suggested, screening of the substructures can include applying one or more filters in addition to screening for a target property (e.g., antimicrobial activity against a target microbe). The filters are typically used to remove substructures from further consideration. Filtering can be accomplished using computer modules or manual techniques. With reference to FIG. 1A, the TPML module 128, for example can be employed to screen substructures for predicted toxicity. The initial substructures can be screened to remove substructures with undesirable chemical attributes such as PAINS or Brenk substructure by, for example, chemical attribute module 130. The initial substructures can also be screened to remove substructures with similarity to other chemical compounds (e.g., known antimicrobial compounds) by, for example, chemical similarity module 132. As examples, initial substructures may be removed if the initial substructures exhibit one or more of: 1) predicted cytotoxicity above a threshold; 2) PAINS or Brenk substructures; or 3) structural similarity to compounds that exhibit activity against the target microbe. [0328] For creating and/or identifying substructures disclosed herein, filters were applied to help create and/or identify structurally novel and selective substructures with no chosen chemical liabilities. As shown in FIG.4, a series of filters was implemented to further screen the initial chemical substructures. Initial chemical substructures were eliminated from consideration where the chemical substructures were predicted to be cytotoxic (cytotoxicity prediction score > 0.2) by any of the three human cell cytotoxicity models (e.g., the TPML module 128). Initial chemical substructures were FIG.1 113 Docket No.: BI-11213-PCT eliminated if the substructures contained pan-assay interference substructures (PAINS) or Brenk substructures, which are associated with unfavorable properties such as promiscuous binding, toxicity, and metabolic instability. Third, initial chemical substructures were eliminated from consideration if they weren’t chemically structurally distinct from known antibiotics. In particular, initial substructures were removed from further consideration if they had a Tanimoto similarity relative to one or more known antibiotics below a threshold (e.g., < 0.5). The known antibiotics included a set of 559 antibacterial compounds. The numbers of initial chemical substructures passing these filters to be considered active chemical substructures were 668,874 and 1,159,130 for S. aureus and N. gonorrhoeae, respectively (see FIG.4). [0329] According to an aspect of this disclosure, the active substructure(s) are used as guides to identify and/or create antimicrobial compounds, see 154 or FIG. 1B. In one aspect, known compounds can be searched to identify compounds that have the active substructure(s) and can be tested to determine if the compounds with the active substructure(s) exhibit antimicrobial activity against the target microbe. In another aspect, compounds having the active substructure(s) can be created/generated by adding chemical groups to the active substructure(s) to form compounds that can be tested to determine if the compound with the active substructure(s) exhibit antimicrobial activity against the target microbe. Such identification and/or creation can be at least partially accomplished with, for example, a compound module 134 that includes, for example, an identification module 136 and/or a generation module 138 as shown in FIG.1A. [0330] For finding known compounds, searches of libraries of known compounds can be performed to find compounds having the active substructure(s). If desired, the FIG.1 114 Docket No.: BI-11213-PCT compounds having the active substructure(s) can be reduced by applying filters. For example, the identified compounds can be provided to the trained machine learning model and only those compounds that have above a threshold likelihood of providing antimicrobial activity may be further tested. Thus, the modules 126, 128, 130 and 132 described within the screening module 120 or similar modules may be used to filter compounds, for example with a compound screening module or simply screening module, in the same way they were used to filter substructures. As such, a reference to at least one type of module can refer to one or multiple modules that have a similar or same functionality. Moreover, the identification module 136 can include an APML module like the APML module 126 of the screening module 120, a TPML module like the TPML module 128 of the screening module 120, a chemical attribute module like the chemical attribute module 130 of the screening module 120, and a chemical similarity module like the chemical similarity module 132 of the screening module 120. Further, filtering of compounds can be performed similarly. [0331] For identifying at least some of the antimicrobial compounds of the present disclosure, multiple filters were applied. Only compounds that were predicted to be antibacterial (prediction score > 0.1), were predicted to be non-cytotoxic (cytotoxicity prediction score < 0.5), did not contain PAINS or Brenk substructures, and were distinct from known antibiotics (Tanimoto similarity < 0.5) were further researched. Applying these filters to more than a million (e.g., 6,138,200) compounds available from various sources resulted in 144 compounds representing 77 substructures that were procured for empirical testing against methicillin-susceptible S. aureus (MSSA) RN4220 and 66 compounds representing 27 substructures for testing against N. gonorrhoeae ATCC FIG.1 115 Docket No.: BI-11213-PCT 49226 (see FIG.5). It was found that 26 compounds inhibited the growth of S. aureus and 7 inhibited the growth of N. gonorrhoeae at 50 μM, resulting in working discovery rates of 18.0% and 10.6%, respectively (see FIG. 5, FIGs. 6A-6M, FIGs. 7A-7D (compounds provided with Tanimoto similarities to closest known antibiotic)). [0332] Notably, substructures I and II described herein, were represented in four active compounds (see FIG. 8). The minimum inhibitory concentrations (MICs) of these active compounds ranged from 2 to 16 μg/mL and both compounds with substructure I were equally effective against MSSA RN4220 and MRSA BAA1556 – a member of the USA300 clade associated with widespread community transmission (see FIG.9 with graphs corresponding compounds as numbered in FIG. 8). The active compounds exhibited a range of selective inhibition of bacterial growth, with half-maximal inhibitory concentration (IC50) values of 2 to >128 μg/mL for substructure I-containing compounds and 32 to >128 μg/mL for substructure II-containing compounds when tested against HEK293, HepG2, HSkM and IMR90 cells (see FIG.9). The therapeutic indices (ratio of human cell IC50 to MIC values) thus ranged between 2 to > 20 for compounds based on substructure I, and 2 to 8 for those based on substructure II. [0333] To identify compounds with higher selectivity indices, a search for analogs of the compounds containing substructure I and substructure II was performed for purchasable compounds. Nine analogs containing substructure I (with predicted antibacterial score > 0.1), and none containing substructure II were found. Five of the nine substructure I-containing analogs were active at 32 μg/mL against both MSSA RN4220 and MRSA BAA1556; however, none exhibited higher therapeutic indices (see FIGs.10 and 11). FIG.1 116 Docket No.: BI-11213-PCT [0334] For creating at least some of the antimicrobial compounds (see 154 of FIG.1B) of the present disclosure, generative techniques are used to add chemical substructures to the active substructure(s). Like the generation of initial substructures, according to one protocol, a set of atoms such as C, N, O, F, I, Cl, Br, S, or any combination thereof can be identified and used to create all or a subset of chemically possible and/or stable substructures having a preselected number (e.g., at least 8, 9, 10 or more, but no greater than 25, 19, 18 or less) of such atoms where those substructures are suitable to be bonded to the initial active chemical substructures. Such generation can be manual but is typically accomplished with one or more generative modules such as the generative module 138 of FIG. 1A. As examples, the one or more generative modules 138 can include a genetic generative module, a fragment generative module, or both to create a plurality of candidate compounds using generative techniques. The active chemical substructures can be provided to the one or more generative modules 138 and the one or more generative modules can create candidate compounds by outputting added chemical substructures that can be appropriately bonded to the initial active substructures. [0335] The genetic generative module (see FIG. 12A) is an algorithm that provides a computational framework that starts with a substructure and/or compound of interest and generates de novo candidate compounds by adding, replacing, or deleting atoms and functional groups. The genetic generative module includes rules that guide the creation toward forming chemically reasonable candidate compounds based on the substructure and/or compound that is provided to the module. Once a first set of candidate compounds is produced, those compounds can be, if desired, provided to the FIG.1 117 Docket No.: BI-11213-PCT genetic generative module to form further candidate compounds. An example of a genetic generative module is referred to as CReM (chemically reasonable mutations), which is an open-source Python framework usable to generate chemical structures using a substructure-based approach. [0336] During generation of compounds, if desired, the compounds generated can be reduced by applying filters. For example, the identified compounds can be provided to the trained machine learning model and only those compounds that have above a threshold likelihood of providing antimicrobial activity may be further tested. Thus, the modules 126, 128, 130 and 132 described within the screening module 120 or similar modules may be used to filter compounds in the same way they were used to filter substructures using, for example, a compound screening module or screening module. As such, a reference to at least one type of module can refer to one or multiple modules that have similar or same functionality. Moreover, the generation module 136 can include an APML module like the APML module 126 of the screening module 120, a TPML module like the TPML module 128 of the screening module 120, a chemical attribute module like the chemical attribute module 130 of the screening module 120, and a chemical similarity module like the chemical similarity module 132 of the screening module 120. Further, filtering of compounds can be performed similarly. [0337] For compounds of the present disclosure, additions were made by sampling from up to 1,557,992 distinct structures containing identified organic elements (C, N, O, S, P, F, Cl, Br, I, B) from ChEMBL44, version 22 a manually curated database of bioactive molecules with drug-like properties. The genetic generative module employed the APML module to attain prediction scores for antibacterial activity, and then compounds FIG.1 118 Docket No.: BI-11213-PCT having prediction scores above a threshold (prediction scores > 0.3 for S. aureus and > 0.7 for N. gonorrhoeae) were successively provided as inputs for the next round of molecule generation. At each round, measures were taken to assure that all generated compounds contained either substructure I or substructure II and did not display PAINS or Brenk alerts. Additionally, compounds were penalized and/or removed if they included structures that were similar to known antibiotics or had high calculated synthetic complexity (See FIG.12B). After five rounds of selection, where each round resulted in progressively higher-scoring compounds (See FIG. 13), 1,062,567 and 518,203 compounds were generated for S. aureus and N. gonorrhoeae, respectively. To obtain a more experimentally tractable list of the most promising molecules, these compounds were further filtered based on higher thresholds for predicted antibiotic activity, predicted cytotoxicity, Tanimoto similarity to known antibiotics and the training set, and a synthetic accessibility score (based on either the SAScore45, RAScore46 and R244 score from Spaya Iktos47; see methodologies further described herein). This resulted in 428 and 285 CReM-generated compounds for S. aureus and N. gonorrhoeae, respectively (see FIGs. 14 and 15 (noting that FIG. 15 refers to substructure I as Fragment F1 and substructure II as Fragment F2). [0338] The fragment generative module can be a design-driven approach based on a generative deep learning system. The system typically includes a fragment-based variational autoencoder (FVAE) trained on a library of compounds (e.g., 10,000 to 1 billion compounds). The FVAE architecture (see FIG. 16) typically includes a graph convolutional network encoder module in which molecular graphs of the library of compounds are encoded (e.g., as latent vectors) as well as a recurrent graph decoder FIG.1 119 Docket No.: BI-11213-PCT module, in which the latent vectors are converted back to molecular graphs. The FVAE starts with a substructure and expands on it until it converges and becomes a compound. Novel compounds are generated from the FVAE by sampling the latent space generated from an input substructure (e.g., by creating random latent vectors and passing them the decoder). [0339] For compounds of the present disclosure, the FVAE was trained on all 1,686,695 compounds from ChEMBL44, version 22, and is based on a prior junction-tree variational autoencoder model. By applying the FVAE, 7,283,458 and 6,937,678 candidate compounds were generated containing substructure I and substructure II, respectively. Filtering the resulting compounds as described herein relative to antibiotic activity, cytotoxicity, PAINS and/or Brenk substructures, and/or structural dissimilarity resulted in 678 candidate compounds for S. aureus and N. gonorrhoeae, respectively (see FIGs.15 and 17). [0340] To better understand the chemical matter produced by our generative models, the resulting compounds’ physicochemical properties were assessed (see FIG. 18). It was found that CReM-generated compounds typically possessed more limited molecular weights, calculated partition coefficient (clogP), and calculated topological polar surface area (TPSA) values, than did FVAE-generated compounds. All compounds generated for substructure I exhibited lower molecular weights, larger clogP values, and lower TPSA values than do typical Gram-positive antibiotics, for which the respective mean values have been calculated to be 813 Da, 2.1, and 243 A2 49. For Gram-negative antibiotics, the respective mean values have been calculated to be 414 Da, -0.1, and 165 A2. Thus, the FVAE-generated compounds for substructure FIG.1 120 Docket No.: BI-11213-PCT II were substantively larger than CReM-generated compounds, which were within the molecular weight range of known Gram-negative antibiotics. [0341] After discovery (e.g., identification and/or generation) of compounds, the candidate compounds are typically tested (see 156 of FIG. 1B) to determine which of the candidate compounds exhibit desired activity. Such testing is typically done in a laboratory. However, depending on the size of the library of discovered (e.g., identified and/or generated) compounds, as part of the testing, it may be desirable to apply further filters to reduce the number of compounds that are to be tested. Such filtering can be accomplished with a compound testing module 140 as shown in FIG.1A. For example, the testing can be performed on a subset of compounds that exhibit properties such as antimicrobial prediction scores above a threshold (e.g., ≥ 0.7) as determined by the machine learning model, dissimilarity of compounds within the library and/or relative ease of synthesis. Thus, the modules 126, 128, 130 and 132 described within the screening module 120 or similar modules may be used to filter compounds in the same way they were used to filter substructures. As such, a reference to at least one type of module can refer to one or multiple modules that have similar or same functionality. Moreover, the compound testing module 140 can include an APML module like the APML module 126 of the screening module 120, a TPML module like the TPML module 128 of the screening module 120, a chemical attribute module like the chemical attribute module 130 of the screening module 120, and a chemical similarity module like the chemical similarity module 132 of the screening module 120. Further, filtering of compounds can be performed similarly. FIG.1 121 Docket No.: BI-11213-PCT [0342] For the compounds disclosed herein, a threshold antibacterial score greater than 0.7 was employed to reduce the number of compounds along with a prioritization of compounds that were structurally dissimilar from each other (see FIG. 19). This resulted in 119 compounds, which were evaluated by chemical synthesis providers. Attempting the synthesis of 34 substructure I-based and 10 substructure II-based compounds resulted in the successful synthesis of four substructure I-based compounds (compounds SA1-SA4 of FIG.20, Synthesis of FIG.21) and two substructure II-based (compounds NG1-NG2 of FIG.20, Synthesis of FIG.21) with high purity (>95%). [0343] Testing of the compounds of present disclosure involved testing the ability of the compounds to reduce and/or kill the target microbe(s). Generally, this involved exposing the target microbe(s) to the compound(s) for a period of time followed by determining the reduction in the amount of the target microbe(s). Such testing typically results in a score that identifies, within tolerances, the amount of the target microbe(s) that have been killed. This can be done for any of the microbes discussed herein. [0344] For example, several of the compounds of the present disclosure were tested to determine their ability to reduce strains of S. aureus and N. gonorrhoeae. The four structure I-based compounds inhibited the growth of S. aureus RN4220 at concentrations ≤ 32 μg/mL, and one structure II-based compound, NG1, but not NG2, inhibited the growth of N. gonorrhoeae ATCC 49226 – resulting in promising working true discovery rates of 100% and 50%, respectively. Determining the MIC, IC50 values, and TIs of the active compounds as before, it was found that compounds SA1 and NG1 possessed the most favorable MIC values (both 0.5 μg/mL against S. aureus and N. gonorrhoeae, respectively) and IC50 values (5 to 8 μg/mL and 25 to 128 μg/mL, FIG.1 122 Docket No.: BI-11213-PCT respectively) against HEK293, HepG2, HSkMC and IMR90 cells, resulting in TIs of 10 to 16 and 50 to 256, respectively (see FIG. 22 and FIGs.23A-23C). The potency and selectivity of the other validated compounds were less than that of SA1 and NG1 (See FIG.22); therefore, further investigation of SA1 and NG1 became a focus. Both SA1 and NG1 are structurally dissimilar from active compounds in the training data and are small but non-Lipinski conforming (see FIG. 24). Interestingly, compound SA1 was generated by CReM, while compound NG1 was generated by FVAE, illustrating the utility of these two different generative machine learning models. [0345] Spectrum activity of the candidate compounds can also be tested. To assess the spectrum of activity of SA1 and NG1, each compound was tested against several Gram- positive and Gram-negative bacterial species. It was found that SA1 exhibited broad spectrum activity against Gram-positive bacteria, including Bacillus subtilis, vancomycin susceptible Enterococcus faecalis, and vancomycin-resistant Enterococcus faecium, but did not inhibit the growth of Gram-negative bacteria including E. coli, Acinetobacter baumannii, Klebsiella pneumoniae, or Pseudomonas aeruginosa. The compound had limited activity against Haemophilus influenzae and Mycobacterium tuberculosis (MIC of 32 μg/mL), and inhibited N. gonorrhoeae at 16 μg/mL (see FIG. 25A and FIGs. 23A-23C). SA1 also inhibited the growth of 39 Gram-positive multidrug-resistant isolates from the CDC Antimicrobial Resistance Isolate Bank (ARB), including isolates from the vancomycin-intermediate S. aureus (VISA), aminoglycoside/tetracycline resistant (ATR), tedizolid/linezolid (oxazolidinone)- resistant staphylococci (TLZD), and vancomycin resistance enterococci (VRE) panels, exhibiting promising MICs ranging between 0.5 and 8 μg/mL for all isolates (see FIG. FIG.1 123 Docket No.: BI-11213-PCT 25B and FIGs.23A-23C). In contrast, NG1 exhibited narrow-spectrum activity against N. gonorrhoeae (see FIG. 25A). Further testing demonstrated that NG1 exhibited potent activity against highly drug-resistant N. gonorrhoeae strains, including the first pan-resistant strain found in the U.S. in 2023 (see FIG. 25C). NG1 was also active against Neisseria meningitidis – the only other pathogenic Neisseria species – and not against the human commensal species of Neisseria cinerea or Neisseria mucosa (see FIG.25C and FIGs.23A-23C). These data indicate that de novo designed compounds exhibit antibacterial against multidrug-resistant and pathogenic strains, suggesting that the compounds may act through novel mechanisms of action to which resistance has not yet evolved. [0346] Compounds of the present disclosure were also investigated for the mechanism of action, toxicology and in vivo efficacy. Time-kill experiments demonstrated that SA1 substantively decreased log-phase MSSA RN4220 colony forming units (CFUs) as early as 2 hours post-treatment (see FIG. 26A), exhibiting faster bactericidal activity than that of vancomycin, a first-line drug against S. aureus infections. Additionally, the minimum bactericidal concentration (MBC) of SA1 was 2 μg/mL for both MSSA RN4220 and MRSA BAA1556 (see FIG. 26B). In spontaneous mutant generation experiments on solid agar, a low frequency of resistance (~3.6 × 10-7) at 4× MIC on solid agar was observed, and no colonies emerged at 8× MIC on solid agar. These findings suggested a mechanism capable of evading substantial resistance and led to the hypothesis that SA1 targets the bacterial cell membrane, as has been previously observed for compounds with such properties. To test this hypothesis, the effect of SA1 on the proton motive force (PMF) was assessed using the potentiometric fluorophore, FIG.1 124 Docket No.: BI-11213-PCT DiSC3(5) (3,3-dipropylthiadicarbocyanine iodide)5,8,51, which displays an increase in fluorescence when the membrane potential, ΔΨ, is disrupted and a decrease in fluorescence when the pH gradient, ΔpH, is dissipated. It was found that cells treated with SA1 exhibited fluorescence quenching of DiSC3(5), suggesting that SA1 dissipates the ΔpH component of the PMF (see FIG.26C). Consistent with this finding, increases in the optical density of MSSA RN4220 and MRSA BAA1556 treated with SA1 in high pH media (see FIG.26D) were observed, indicating that dissipation of ΔpH is sufficient to explain SA1’s antibacterial activity. [0347] Further toxicology studies measuring human red blood cell hemolysis and bacterial mutagenesis indicated that SA1 was not hemolytic or mutagenic (FIGs. 27A and 27B). SA1 was tested in a mouse model of MRSA skin infection using MRSA BAA1556. Mice were rendered neutropenic and inflicted with skin wounds. After inoculation of ~105 CFU of MRSA USA300, each wound was topically treated with SA1 (1% w/v) six times before the wounds were excised for CFU determination 25 hours after infection. Treatment with SA1 significantly decreased the mean bacterial load by ~2 logs relative to vehicle (one-sided Mann-Whitney U-test, p=0.0022), similar to the efficacy of fusidic acid, a positive control used in the clinical treatment of staphylococcus infections (see FIG.26E). The decrease in bacterial load found for SA1 was also similar to, or better than, that of complestatin and corbomycin, as well as other antibiotic candidates that have recently been discovered. Together, these findings suggest the potential of SA1 to be further developed for increased antibacterial activity and clinical usage. FIG.1 125 Docket No.: BI-11213-PCT [0348] Similar to SA1, the mechanism of action of NG1 was investigated by first examining whether the compound was bactericidal. In a time-kill experiment, NG1 exhibited concentration-dependent killing, with efficacy similar to that of azithromycin (FIG.28A). Additionally, the minimum bactericidal concentration was 1 μg/mL (FIG. 28B). In suppressor mutant generation experiments on solid agar, the frequency of resistance against NG1 was 4.3 × 10-8 at 8× MIC. The spontaneously-arising NG1- resistant isolates retained susceptibility to ceftriaxone, azithromycin, and ciprofloxacin, with unchanged MICs relative to the ancestral strain (see FIG.27D). The lack of cross- resistance was supported by checkboard assays demonstrating that NG1 was indifferent (neither synergistic nor antagonistic) to ceftriaxone, fosfomycin, and CCCP – indicating that NG1 does not act similarly to other cell wall- and membrane PMF-targeting antibiotics (See FIG. 27E). Indeed, unlike SA1, NG1 did not alter the membrane potential in a DiSC3(5) assay (See FIG.27C). [0349] To further investigate the mode of action, NG1 was tested to determine if treatment altered membrane fluidity using a Laurdan dye assay7, where cells with decreased membrane fluidity exhibit increases in Laurdan fluorescence and vice-versa. Treatment of N. gonorrhoeae cells with NG1 resulted in a modest increase in Laurdan fluorescence, suggesting that NG1 may act, in part, by decreasing membrane fluidity (FIG.28C). It was hypothesized that this would compromise membrane integrity and this hypothesis was tested by measuring the uptake of a hydrophobic fluorescent probe, 1-N-phenylnaphthylamine (NPN), which fails to cross intact outer membranes. NG1 treatment resulted in a significant increase in NPN fluorescence, suggesting that the outer membranes of cells were indeed compromised (FIG. 28D). NG1-treated N. FIG.1 126 Docket No.: BI-11213-PCT gonorrhoeae cells also exhibited increased fluorescence of SYTOX Green, a DNA- intercalating dye that only penetrates cells with compromised membranes (FIG.28E), further supporting the suggestion that membrane damage leads to cell death. Together, these findings suggest distinct mechanisms of action of SA1 and NG1, illustrating the ability of our deep learning approach – which is substantially agnostic to mechanisms of action – to produce structurally-dissimilar compounds with divergent mechanisms of action. [0350] As with SA1, toxicology studies measuring human red blood cell hemolysis and bacterial mutagenesis indicated that NG1 was not hemolytic or mutagenic (Figs. 27A and 27B). The efficacy of NG1 was tested in a mouse model of N. gonorrhoeae vaginal infection. Here, ovariectomized and estradiol-treated mice were intravaginally inoculated with N. gonorrhoeae ATCC 49226. Two hours later, mice were given their first dose of intravaginal NG1 (1%), ceftriaxone (0.1%), or vehicle control, followed by four additional doses within a 24 hour period. Mice treated with NG1 exhibited a significant decrease in vaginal bacterial load (two-sided Mann-Whitney test, p=0.0120) (FIG. 28F). These results support the potential clinical relevance of NG1 and related compounds. [0351] Once desired compounds are identified or created, particularly those compounds that are validated as discussed herein, structural analogs of those compounds can be synthesized and tested to help understand the chemical space or class of compounds that might also have similar activity. Several of the compounds of the present disclosure were created as structural analogs to SA1 and NG1 to explore the significance of the substructures I and II. FIG.1 127 Docket No.: BI-11213-PCT [0352] Building on the high selectivity of SA1 and NG1 (FIG.22), as well as to further test the functional significance of substructure I and II, an investigation of the structure- activity space of both compounds was explored by synthesizing and testing structural analogs. For SA1, modifications were made to the position and/or type of halogen atoms (Cl or F), the position of the benzoic acid attached to the oxygen or replaced the benzene ring with a pyridine ring. Of the ten analogs synthesized with these modifications, it was found that five exhibited the same potency as SA1 with an MIC of 0.5 μg/mL when tested against MSSA RN4220 (FIG. 29A and 29B). The IC50 values of all analogs tested against HEK293, HepG2, HSkM cells were also comparable to that of SA1 (FIG. 29C), further supporting that substructure I defines a structural class of compounds with antibacterial activity. [0353] For NG1, four analogs in Enamine’s REAL Space library (see FIG. 30A) were procured. One of the four compounds, NG2 (i.e., NG1 analog), was active against N. gonorrhoeae with an MIC of 4 μg/mL; additionally, its IC50 values against HEK293, HepG2, HSkM and IMR90 cells were higher than those of NG1 (see FIG. 30B), suggesting promise for further development. NG1 analog’s mechanism of action were tested as above and found that it acted similarly to NG1 (see FIGs.30C, 30D, and 30E). To perform a more systematic structure activity relationship (SAR) analysis of substructure II, 40 additional analogs were synthesized as designed by largely altering the functional groups, connected to the pyrrolidine ring and the amine, respectively (see FIGs. 31A, 31B, and 31C). Testing all analogs, five active molecules against N. gonorrhoeae ATCC 49226 were found, with MIC values between 16 to 410 μg/mL (see FIGs. 31A, 31B, 31C and 31D). Compounds with an Y1 group containing a 2,3- FIG.1 128 Docket No.: BI-11213-PCT dichlorophenyl group were more effective at inhibiting N. gonorrhoeae than those containing a 2,4-dichlorophenyl group, and compounds containing either group were more efficacious than those containing a 2-chlorophenyl or phenyl group alone. Together, these findings support the antibacterial activity of substructure I and substructure II as starting scaffolds for de novo design and suggest routes for additional optimization to further improve the potency and selectivity of generated compounds. [0354] Compounds of Structure VI along with their favorable MIC and/or toxicity data are illustrated in the table in FIG.33A. Compounds of Structure VII along with their favorable MIC and/or toxicity data are illustrated in the table in FIG 33B. Additional compounds active against N. Gonorrhea (i.e., NG22-NG24) along with their favorable MIC and/or toxicity data are illustrated in the table in FIG.33C. [0355] At least one compound of Structure VI (NG10) and at least one additional compound (NG22) exhibited particularly significant efficacy against MDR N. gonorrhoeae strains, including a strain that was found in the U.S. to be non-susceptible or resistant to recommended drugs for treatment (ARB #1281, see FIG.34). Notably, the MICs of NG10 and NG22 were not affected by increased expression of the mtrCDE effux pump, which is responsible for multi-drug resistance in N. gonorrhoeae, nor decreased outer membrane permeability due to porB mutations (see FIG. 34). When evaluating the spectrum of activity, NG10 inhibited the growth of both methicillin- susceptible and methicillin-resistant strains of S. aureus but was not efficacious against any of the other gram-negative bacteria tested, including Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Compound NG22 was even narrower in spectrum, with activity only FIG.1 129 Docket No.: BI-11213-PCT against N. gonorrhoeae. This enforces the potential for ML models trained on organism-specific data to assist researcher in uncovering selective, narrow-spectrum antimicrobials that have traditionally been difficult to identify. [0356] To determine whether they are bactericidal or bacteriostatic, time-kill curves with ATCC 49226 were performed, which demonstrated that NG10 had rapid, concentration-dependent bactericidal effect, with >3-log killing in an hour at 4× agar MIC (see FIG. 35). NG22 was also bactericidal, exhibiting 4-log killing in 4 hours at 4× MIC, which was slower than NG10 but faster than ceftriaxone (FIG. 35). To estimate the rate at which clinical resistance could emerge, the frequency of spontaneous resistance for both NG10 and NG22 was determined. A concentrated, titered stock of N. gonorrhoeae ATCC 49226 was added to GC agar plates containing the compound at 2×, 4×, or 8× agar MIC. After 72 hours of incubation, no resistant colonies emerged on any of the NG10 or NG22 plates, indicating frequencies of resistance less than 8.3 x 10-9 (see FIG.36). The low frequencies of resistance indicate a lack of preexisting antibiotic resistance determinants to NG10 and NG22 in this strain population. In conjunction with the maintained potency in multi-drug-resistant isolates, this finding suggests that NG10 and NG22 act through an orthogonal mechanism of action to existing antibiotics. [0357] Given that NG10 and NG22 had attractive qualities as hit compounds, their efficacy was tested in more complex microenvironments. The microfluidic vagina-on- a-chip (“Vagina Chip”) was employed as a model for testing the candidates due to the use of primary human cells (both vaginal epithelial and uterine fibroblast cells), unique recapitulation of the three-dimensional vaginal environment with tissue-tissue and FIG.1 130 Docket No.: BI-11213-PCT tissue-fluid interfaces, and simulation of fluid flows. The Vagina Chip was recently used to study human vaginal microbial communities under microaerophilic conditions, and here, those conditions were adapted to support Neisseria gonorrhoeae for the first time. Prior to commencing the Vagina Chip experiments, it was ensured that N. gonorrhoeae was not cytotoxic at the relevant concentrations to epithelial cells. The stability of the compounds in the basal and apical media used in the Vagina Chip were also tested. Compound NG22 showed a four-fold increase in MIC after two days of incubation in the basal medium, while NG10’s was unchanged. Thus, NG22 was omitted from subsequent Vagina Chip experiments due to stability concerns. [0358] To begin, the polymeric Vagina Chips were prepared by growing human fibroblasts and vaginal epithelial cells on opposing basal and apical sides of the porous membrane, respectively. After several days of differentiation and growth, the vaginal epithelial cells form a continuous stratified epithelium, which prevents mixing of the apical and basal media. N. gonorrhoeae ATCC 49226 was then added to the apical channel, which mimics the vaginal lumen, and allowed to adhere for two hours. To mimic systemic drug administration, NG10 or ceftriaxone was then added to the basal channel, and bacteria-only negative control chips did not receive any antibiotic. After two days of incubation at 37°C and 5% CO2 under continuous basal flow and intermittent apical flow, quantitative culture was performed of free-floating N. gonorrhoeae and cell-adhered N. gonorrhoeae on vaginal epithelial cells. Both NG10 and ceftriaxone resulted in undetectable levels of both adhered and non-adhered N. gonorrhoeae, while the no-drug controls had a mean adhered bacterial load of 1.56 x 105 CFU/chip and unadhered load of 8.22 x 103 CFU/chip (FIG.37). The reductions in FIG.1 131 Docket No.: BI-11213-PCT N. gonorrhoeae load were significant in both the adhered (p<0.0001, one-way ANOVA with Dunnett’s multiple comparison testing of NG10 and ceftriaxone vs. the untreated control) and unadhered fractions (p=0.0309, one-way ANOVA; p=0.0374 of NG10 vs. untreated and p=0.0403 of ceftriaxone vs. untreated with Dunnett’s multiple comparison testing.) These results support that NG10 can permeate from the interstitial fluid to the vaginal lumen when administered systemically and shows that NG10 retains antibacterial activity without overt human cell toxicity even in complex microenvironments. [0359] Compound NG22 was tested in a mouse model of N. gonorrhoeae vaginal infection. Compound NG22 appeared to be well-tolerated in BALB/c mice, with a maximum tolerated dose of 100 mg/kg, which was the highest dose tested, when given once a day systemically via an intraperitoneal injection (IP), and at least 50 mg/kg when given every 6 hours IP. In vivo testing was then performed, where the efficacy of the test compound NG22 was compared to the positive control of ceftriaxone and negative control of vehicle only. Since N. gonorrhoeae infection is naturally cleared in mice during specific stages of the estrous cycle, the infection was performed in ovariectomized mice that were additionally treated with exogenous 17β-estradiol and received gonococcal-inactive antibiotics to reduce overgrowth of endogenous vaginal flora that occurs with estrogen treatment. The mice were inoculated intravaginally with N. gonorrhoeae ATCC 49226, and treated intravaginally at 2, 6, 10, 18, and 24 hours post-infection. Two hours after the last dose, the animals were sacrificed, and vaginal lavages were performed for quantitative culture. As expected, ceftriaxone treatment resulted in undetectable levels of N. gonorrhoeae while the vehicle control had a median FIG.1 132 Docket No.: BI-11213-PCT N. gonorrhoeae load of 2.0 x 105 CFU/mL. Compound NG22 significantly reduced the median bacterial load by over two logs relative to vehicle (see FIG.38). [0360] Scientific/Experimental Methods, Machines, and Mechanisms [0361] Scientific/Experimental methods, machines, mechanisms, etc. used for validating, determining, analyzing and the like parameters discussed herein are described in detail below. These methods, machines, mechanisms, etc. are provided for describing specifics of the validating, determining, analyzing, and the like performed herein. They are not meant to be limiting relative to an aspect of the present disclosure unless otherwise specifically stated. [0362] Machine learning model: Chemprop is a software package that can be implemented in hardware and that implements directed message-passing neural networks (D-MPNNs). Here, these models were trained on binarized data representing the empirical growth inhibitory activity of substructures and compounds. As described previously, D-MPNNs, which are a form of graph neural networks (GNNs), take as input a simplified molecular-input line-entry system (SMILES) string of a compound and convert it to a molecular graph representation. Graph convolutional operations are applied to each atom and bond, and information from local substructures of the substructure or compound are aggregated. An intermediate vector representation is generated by collapsing the information associated with each bond and atom into a single embedding. This embedding is then concatenated to a list of global biophysical features, such as molecular weight, which are used to potentially improve the predictions made, and the output is then passed to a fully-connected feed-forward neural network. The output of each trained model is a score between 0 and 1, representing the FIG.1 133 Docket No.: BI-11213-PCT probability that the input substructure or compound is antimicrobial (e.g., antibacterial) (0: does not inhibit bacterial growth and 1: inhibits bacterial growth). [0363] The output of an ensemble was taken as the average of all models in the ensemble. In this work, ensembles of 20 binary classification Chemprop models for two bacterial species, S. aureus and N. gonorrhoeae, were trained on 39,312 and 38,765 compounds (as described in detail in Wong et al. and Anahtar et al.), respectively. Hyperparameter optimization was performed, and each ensemble was previously benchmarked. [0364] Chemprop models predicting cytotoxicity against human cells were previously developed and described in Wong et al.; in this work, these models were used to predict the cytotoxicity of a given fragment or compound against human hepatocarcinoma (HepG2), primary skeletal muscle (HSkM), and lung fibroblast (IMR-90) cells. The output of these models is a score between 0 and 1, describing the probability that the inputted compound is cytotoxic (0: non-toxic and 1: toxic). [0365] Substructure and compound libraries: A substructure library comprising 106,212,801 substructures was assembled from the Generated DataBase (GDB, courtesy of Dr. Jean-Louis Reymond at the University of Bern, Switzerland) and the Readily AccessibLe (REAL) substructure database from Enamine. The GDB libraries enumerate all theoretically-possible substructures up to a prespecified number of atoms following chemical stability and synthetic feasibility rules. To compile a set of 11-atom substructures including C, N, O, F, Cl, and S atoms, the entire GDB-1137 (substructures up to 11 atoms including C, N, O, and F atoms, N =26,434,571) were combined and all up-to-11-atom fragments in the GDB-1338 (which includes C, N, O, Cl, and S atoms, FIG.1 134 Docket No.: BI-11213-PCT N = 1,089,000). Up-to-17 atom fragment from the GDB-1739,59,60 (which includes C, N, O, S and halogen atoms, sampling a N = 50,000,000 random subset) and the entire FDB-1760 (N = 10,351,204) were also assembled. The REAL substructures (version October 5, 2022, N = 18,338,026) were obtained from the Enamine database. [0366] To experimentally assess chemically diverse compounds containing the above substructures, a database of 6,937,349 compounds was assembled from two large purchasable libraries: 799,149 compounds from the Broad Institute and 6,138,200 commercially-available compounds from MolPort, MayBridge, and Ambinter. [0367] Identification and selection of substructures and compounds associated with antimicrobial activity: All 106,212,801 substructures were scored using the trained S. aureus ensemble, and 45,858,026 substructures, containing readily-accessible substructures from Enamine’s REAL substructure database, were scored using the trained N. gonorrhoeae ensemble, as described above. All 6,937,349 compounds were scored using both S. aureus and N. gonorrhoeae ensembles. For the analysis, three fragments/substructures representative of known antibiotics were encoded using the following SMILES strings: nitrofuran: ‘O=[N+](O)c1ccco1’; fluoroquinolone: ‘O=C(O)c2c[nH]c1ccc(F)cc1c2=O’; and carbapenem: ‘O=C(O)C1=CCC2CC(=O)N12’. Compounds containing these scaffolds were identified in a manually-compiled set of 559 known antibiotics and antiseptics. Compounds containing the substructures were identified using RDKit’s HasSubstructMatch function, and the known antibacterial compounds were subsequently scored using either the S. aureus or N. gonorrhoeae ensembles. It was found that the prediction scores for compounds correlated with the prediction scores of FIG.1 135 Docket No.: BI-11213-PCT the substructure alone, supporting the performance of an algorithm that identifies substructures with high predictive scores for the discovery and design of selective antimicrobial (e.g., antibacterial) compounds. [0368] As detailed in the main text and GitHub repository, the approach to substructure selection and compound testing involved multiple steps. For each of S. aureus and N. gonorrhoeae, substructures with antimicrobial activity prediction scores > 0.05 or > 0.1 were retained in the GDB and REAL libraries, respectively. Of these substructures, those with cytotoxicity prediction scores < 0.5 across all three human cell types (HepG2, HSkMC, and IMR90) were retained. Substructures were then tested for the presence of PAINS or Brenk substructures using RDKit’s FilterCatalogParams.FilterCatalogs.PAINS and FilterCatalogParams.FilterCatalogs.BRENK properties, respectively. To focus on structurally novel substructures, only substructures with maximum Tanimoto similarity < 0.5 with respect to the aforementioned set of 559 known antibiotics, as computed using RDKit’s FingerprintSimilarity function, were retained. Here, Tanimoto similarity was calculated using Morgan fingerprints, with radius equal to 2 and number of bits equal to 2048. The remaining substructures were matched to compounds using RDKit’s HasSubstructMatch function. Matched compounds were considered if they had an antibacterial activity prediction score > 0.1, and matched compounds were filtered in the same way for cytotoxicity and structural novelty as described for fragments above. [0369] De novo design of compounds with generative models. For the genetic algorithm based on CReM described herein, a modified version of CReM21 was implemented. For each run of the algorithm, the SMILES string of a fragment and FIG.1 136 Docket No.: BI-11213-PCT molecule containing the fragment/substructure was provided as input; the former was provided in order to ensure that all generated compounds possessed the substructure using RDKit’s HasSubstructMatch function, and the latter was provided as a seed. For substructure I, the SMILES strings used were “C(C1=CNC2=C1C=CC=C2)C1=CC=CC=C” and “CC1(CNC(=O)CC(c2c[nH]c3ccc(Cl)cc23)c2ccc(Cl)cc2)CCCO1”, respectively; for substructure II, the SMILES strings used were “CC(=O)NC1CCN(C2=CC=C(Cl)C=C2Cl)C” and “Clc1ccc(c(c1)Cl)N1CC[C@@H](C1)NC(=O)c1cn[nH]n1”, respectively. By default, CReM provides two methods: ‘grow’ and ‘mutate’ (as implemented in the CReM Python package). Ranges for parameter combinations were provided as additional input. Parameter combinations for grow algorithms included max_atom (4, 6, 8, and 10 were used), min_atom (0 was used), and radius (2 and 3 were used), while the parameter combinations for mutate algorithms included the max_size 622 (4, 6, 8, and 10 were used), min_size (0 was used), radius (2 and 3 were used), min_inc (-2 was used), and max_inc (2 was used). All possible combinations of these parameters were considered using a full grid search. For a given parameter set, the algorithm proceeded as follows: (i) The original molecule was used to generate de novo molecules with either the grow or mutate function from CReM, and molecules that did not contain the original fragment were discarded. (ii) Compounds containing PAINS and Brenk substructures were excluded. (iii) Chemprop scores for the resulting compounds were calculated using either the S. aureus or N. gonorrhoeae ensemble. (iv) If the user-defined scoring method was set to ‘regular score’, then the compounds were ranked according to the FIG.1 137 Docket No.: BI-11213-PCT Chemprop models (chempropsco). If not, modified scores that incorporate additional criteria were calculated. The additional criteria included the following variables: SAScore (predicted synthesizability score), tansim (Tanimoto similarity to known antibiotics), hepg2 (predicted toxicity score for HepG2 cells), and prim (predicted toxicity score for HSkM cells). To improve speed, prediction scores from the IMR90 cytotoxicity ensemble were not considered as an additional variable here, but all generated compounds were eventually filtered based on cytotoxicity prediction scores from all three cytotoxicity ensembles (as described in Down-selection of generated compounds for synthesis and testing below). Modified scores (adj_score) were calculated based on the original score (chempropsco) and the additional variables according to the formula: adj_score = (2.0 * chempropsco) - ((sascore / 10.0) + tansim + hepg2 + prim). (v) Finally, to seed the next iteration of the algorithm, the number of compounds generated were calculated and scored in steps (i)-(iv) above (Ngen) and ubmax_atom_range ≥ 8, then Ntop = 2 and Nrand = 1; else Ntop = 5 and Nrand = 5. If Ngen ≤ Ntop + Nrand, then all Ngen compounds were used to seed the next iteration. Otherwise, the Ntop highest-scoring compounds among the Ngen generated compounds, as well as Nrand other randomly chosen compounds among the Ngen generated compounds were used to seed the next iteration. [0370] As detailed herein, a total of 1,062,567 and 518,203 compounds were generated using substructure I for S. aureus and fragment substructure II for N. gonorrhoeae, respectively. The exemplary FVAE algorithm described herein starts with substructures associated with specific properties of interest (e.g., antibacterial activity) and expands these substructures (e.g., substructures I and II) into compounds. It uses a FIG.1 138 Docket No.: BI-11213-PCT rationale-conditioned molecular graph generator as a variational autoencoder, which completes a compound, G, given a substructure, S. Since each substructure (S) may yield many different compounds, a latent variable, z, is introduced to generate diverse outputs: where P model includes a graph encoder and a graph decoder. In one example, the encoder is a message passing neural network (MPNN) which learns the approximate posterior for variational inference. In the graphical representation of each compound or substructure, each atom or bond is represented by a one-hot encoding of its atom or bond type. The encoder then uses plural (e.g., three) message-passing layers, followed by an average pooling operation, to transform the initial graph representation into a 20-dimensional latent vector, ^". The decoder then generates a molecule (a molecular graph) according to its breadth-first order. In each step, the model generates a new atom and all its connecting edges. During generation, a queue was maintained and it contained frontier nodes in the graph with neighbors to be generated. Let ^t be the partial graph generated by step t. To ensure that the full molecule, G, contains S as a subgraph, the initial state of ^0 = ^ was set and all the leaf atoms (atoms with degree = 1 in the graph) were put in the queue. In each generation step, the decoder first runs an MPNN over the current graph to compute an atom representation, ℎ^, for each atom, ^. As an example, suppose that the first atom in the queue is ^. The decoder then expands the current molecule using plural (e.g., three) decision steps: FIG.1 139 Docket No.: BI-11213-PCT 1. Predict whether there will be a new atom attached to ^. The probability of this expansion step is predicted based on the latent vector, ^G, and atom representation of ^: ^v = sigmoid(MLP(hv, zG)). 2. If ^v > 0.5, discard ^ and move on to the next node in the queue. Otherwise, create a new atom, ^, predict its atom type, and append it to the queue. 3. Predict the bond type between ^ and other leaf nodes in the queue. Since atoms are generated in breadth-first order, there are no bonds between ^ and atoms not in the queue. To fully capture edge dependencies, the bonds between ^ and atoms in the queue are predicted sequentially, and the representation of ^ is updated when new bonds are added to the substructure. [0371] The FVAE was pre-trained on 1,686,695 molecules from ChEMBL (version 22) to enable the model to generate realistic molecules. Each training example was a pair, (S, G), where S is a random connected subgraph of a molecule G with up to 15 atoms. The generative model was trained to maximize the likelihood of the ground truth compound G given substructure S, using the following hyperparameters: hidden_size = 400, batch size = 16, MPN depth = 3, learning rate = 1e-3, optimizer = Adam, and epoch = 20. A total of 7,283,458 and 6,937,678 molecules were generated using input substructure I for S. aureus, and substructure II for N. gonorrhoeae, respectively. [0372] Down-selection of generated compounds for synthesis and testing: For substructures I and II, both algorithms generated a total 15,801,906 compounds. All compounds were down-selected based on (i) de-duplication of SMILES, (ii) predicted antibacterial score, (iii) maximum Tanimoto similarity with respect to the set of known antibiotics as well as all active antibacterial compounds in the respective training set, FIG.1 140 Docket No.: BI-11213-PCT (iv) synthesizability score (SAscore or RAscore), and (v) predicted HepG2 and/or HSkM cytotoxicity score. Both SAscore and RAscore were used only to sample different synthetic accessibility scoring approaches. [0373] For substructure I, CReM-generated compounds were 707 down-selected using predicted antibacterial score > 0.3, SAScore < 3, Tanimoto similarity < 0.5, and HepG2 and HSkM cytotoxicity score < 0.2. For substructure II, CReM compounds were down selected using predicted antibacterial score > 0.7, SAScore < 3, Tanimoto similarity < 0.5, and HepG2 and HSkM cytotoxicity score < 0.2. Compounds that contained a β- lactam motif, as defined by those returning True using HasSubstructMatch() with the molecule described by 'O=C1CCN1', were additionally filtered out. For substructure I, FVAE generated-compounds were filtered using predicted antibacterial score > 0.3, RAScore > 0.8, Tanimoto similarity < 0.4, and HepG2 cytotoxicity score < 0.2. The same filters, except predicted antibacterial score > 0.8, was applied for substructure II. This resulted in 428 (CReM) and 169 (FVAE) compounds for substructure I and 285 (CReM) and 678 (FVAE) compounds for substructure II. To shortlist these compounds further for chemical synthesis and testing, all CReM and FVAE compounds with predicted antibacterial score > 0.7 were selected. The FVAE compounds were additionally filtered to have a predicted HSkM cytotoxicity score < 0.2. All compounds were then filtered for dissimilarity between themselves by computing Tanimoto similarity scores. For this, the highest-scoring compound was selected, and each remaining compound was assessed. If the Tanimoto similarity was < 0.75 to the already-selected compound list, then the compound was added to the list of selected compounds until 40 compounds remained for each group. A single compound FIG.1 141 Docket No.: BI-11213-PCT overlapped between the CReM- and FVAE-generated groups, resulting in 79 and 80 compounds for each group. Approximately 15 chemical vendors were consulted for synthesis, and six molecules were successfully synthesized. [0374] Visualization with t-SNE. t-SNE plots were generated using scikit.learn’s TSNE() function with perplexity 30, Jaccard distance as the metric, and PCA initialization. Molecules were represented as Morgan fingerprints using RDKit’s GetMorganFingerprintAsBitVect() function with radius 2 and number of bits 2048. [0375] Code availability. A code platform for reproducing all analyses in this work is available via the GitHub repository https://github.com/jackievaleri/fragments_design_ML. [0376] Syntheses [0377] One example of compound synthesis according to the present disclosure is as follows: 1-((1-(2,4-dichlorophenyl)pyrrolidin-3-yl)amino)-1-oxopropan-2-yl (3,4- dichlorophenethyl)carbamate (NG1) [0378] Step A: 1-(2,4-Dichlorophenyl)pyrrolidin-3-amine (24.0 g, 104 mmol) and methyl 2-hydroxypropanoate 1 (40.85 g, 393 mmol) were dissolved in acetonitrile (300 ml), a catalytic amount of N-ethyl-N-isopropylpropan-2-amine (2.7 mL, 15 mmol) was added and the reaction mixture was refluxed for 160 hours. After completion of the reaction, acetonitrile was evaporated under reduced pressure, the residue was diluted with water (200 mL) and extracted with ethyl acetate (3x150mL). The combined organic solution was dried over sodium sulfate and evaporated under reduced pressure to give crude compound 2 as black oil, which was used in the next step without further purification (30.55 g, purity ≈ 60%, yield 58%). [0379] Step B: To a mixture of 1-(((1-(2,4-dichlorophenyl)pyrrolidin-3-yl)amino)oxy)- 1-oxopropan-2-ol (0.52 g, 1.73 mmol, purity 60%, 2) and triethylamine (0.16 mL, 1.11 mmol) in dichloromethane (5 mL), 1,2-dichloro-4-(2-isocyanatoethyl)benzene (0.56 g, 2.59 mmol) was added dropwise under argon atmosphere. The reaction mixture was stirred for 24 hours at room temperature. After completion of the reaction, the volatiles were evaporated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL). The organic solution was washed with water (3x2mL) and brine, dried over sodium sulfate, and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford NG1 (71 mg, yield 13%, purity, >95%, assessed with LC/MS). [0380] 1H NMR (500 MHz, DMSO-d6) δ 8.09 (d, J = 7.1 Hz, 1H), 7.53 – 7.45 (m, 2H), 7.38 (d, J = 2.6 Hz, 1H), 7.31 (s, 1H), 7.25 – 7.16 (m, 2H), 6.90 (d, J = 8.6 Hz, 1H), 4.77 (d, J = 6.9 Hz, 1H), 4.26 (s, 1H), 3.51 (s, 1H), 3.39 (d, J = 8.3 Hz, 2H), 3.32 – 3.26 FIG.1 143 Docket No.: BI-11213-PCT (m, 3H), 2.69 (d, J = 7.4 Hz, 2H), 2.11 (dd, J = 13.1, 6.7 Hz, 1H), 1.81 (s, 1H), 1.23 (dd, J = 9.3, 6.6 Hz, 3H). LC/MS (APSI) m/z [M+H] calculated for C22H24Cl4N3O3: 520.1; found: 520.0. [0381] Another example of compound synthesis according to the present disclosure is as follows: 3-(3,4-dichlorophenyl)-N-(1-(2,4-dichlorophenyl)pyrrolidin-3-yl)-2- methylpropanamide (NG2) [0382] 3-(3,4-dichlorophenyl)-2-methylpropanoic acid (0.1 g, 0.43 mmol) was dissolved in 0.5 mL of 10% HOBt in DMF followed by the addition of 1-(2,4- dichlorophenyl)pyrrolidin-3-amine (0.1 g, 0.43 mmol) and EDC (1.2 mol. eq. to the carboxylic acid). The resulting mixture was shaken for 24 hours at room temperature. Then, CHCl3 (2 mL) was added, and the organic phase was washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The crude was dissolved FIG.1 144 Docket No.: BI-11213-PCT in 0.5 mL of DMSO and further purified by preparative HPLC to afford NG2 (35 mg, yield 19%, purity, >95%, assessed with LC/MS). [0383] 1H NMR (500 MHz, DMSO-d6 δ 7.96 (dd, J = 20.3, 6.5 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.21 (d, J = 8.7 Hz, 1H), 7.12 (dd, J = 19.2, 8.1 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 4.18 (s, 1H), 3.45 (dt, J = 47.3, 8.6 Hz, 1H), 3.21 – 3.03 (m, 2H), 2.96 – 2.62 (m, 1H), 2.58 (d, J = 7.5 Hz, 2H), 2.15 – 1.85 (m, 1H), 1.66 (dd, J = 71.4, 6.4 Hz, 1H), 1.20 – 1.02 (m, 1H), 1.00 (t, J = 6.9 Hz, 3H). LC/MS (APSI) m/z [M+H] calculated for C20H21Cl4N2O: 447.0; found: 447.0. [0384] For the syntheses above: 1H NMR spectra were recorded at 500 MHz (Varian or Bruker spectrometers). 1H chemical shifts are calibrated using residual nondeuterated solvent DMSO: δ = 2.50 ppm. Coupling constants are given in Hz. LC/MS analysis was performed utilizing Agilent 1200 Series LC/MSD system with DAD/ELSD (column Zorbax SB-C181.8 µm 4.6x15mm; solvent A (water, 0.1% formic acid) and solvent B (acetonitrile, 0.1% formic acid); gradient 0% – 100% solvent B, run time, 1.8 min; flow rate, 3 mL/min) and Agilent LC/MSD SL (G6130A), SL (G6140A) mass- spectrometer (APCI mode). All the LC/MS data were obtained using positive/negative mode switching. Experimental Methods [0385] Bacterial strains. The main bacterial strains used in this study include methicillin-susceptible Staphylococcus aureus RN4220 (MSSA), methicillin-resistant Staphylococcus aureus FPR3757 (MRSA USA300; ATCC BAA-1556), and Neisseria FIG.1 145 Docket No.: BI-11213-PCT gonorrhoeae ATCC 49226. These are the strains against which activity is to be measured for the present disclosure. [0386] Other strains used herein include Bacillus subtilis 168, Escherichia coli BW25113, MG1655, JW5503-KanS (ΔtolC832::FRT), and RFM795 (lptD4213), Klebsiella pneumoniae ATCC 13883, Pseudomonas aeruginosa PAO1, Acinetobacter baumannii ATCC 17978 and Mycobacterium tuberculosis MTB H37Ra, ATCC 25177. Additional bacterial isolates were obtained from the CDC & FDA Antibiotic Resistance (AR) Isolate Bank (Atlanta, Georgia). [0387] Chemical compounds. Compounds with high purity (>90%) were procured either from the Broad Institute Center for the Development of Therapeutics (CDoT) or from commercial chemical vendors including BIONET-Key Organics Ltd. (Cornwall, UK), ChemBridge (San Diego, CA), ChemDiv (San Diego, CA), MayBridge (Altrincham, UK), MedChemExpress (Monmouth Junction, NJ), TargetMol (Boston, MA), Vitas-M (Hong Kong, China), and Enamine (Kyiv, Ukraine). Stock solutions and serial dilutions of all compounds were freshly prepared in dimethyl sulfoxide (DMSO; MilliporeSigma D5879), unless stated otherwise. [0388] Known antibiotics were obtained as follows: vancomycin (Fisher Scientific AAJ6279003), valinomycin (Thermo Fisher, V1644), triclosan (MilliporeSigma, 72779), azithromycin (Cayman Chemical, 15004), ceftriaxone (sodium salt hydrate, Cayman Chemical, 18866), Fosfomycin sodium (MilliporeSigma, 34089), CCCP (MedChemExpress, HY-100941), and fusidic acid (Millipore Sigma F0881), all dissolved in DMSO. Kanamycin sulfate (MilliporeSigma, 60615) was dissolved in ultrapure MilliQ-water and ciprofloxacin powder (MilliporeSigma 17850) was FIG.1 146 Docket No.: BI-11213-PCT dissolved in dilute acid (0.1 M HCl). De novo generated compounds and their respective analogs were synthesized and procured from ChemScene (New Jersey, USA, SA1-SA4) and Enamine (Kyiv, Ukraine, NG1-NG2 and analogs). Analogs of compounds containing substructure II (NG1 analogs) were designed and synthesized by CC4CARB (Chemistry Center for Combating Antibiotic-Resistant Bacteria), an NIAID (National Institute of Allergy and Infectious Diseases)-led partnership with RTI (Research Triangle Institute). [0389] MIC and bacterial growth inhibition assays. For S. aureus, a bacterial suspension of ~105 CFU/mL was obtained either by performing a 1:10,000 dilution of an overnight culture, picked from a single colony, or a 1:500 dilution of an OD6000.08 suspension in fresh LB (Becton Dickinson 244620). Cells were seeded in a 96-well plate, with 99 μL of bacteria and one μL of two-fold serially diluted compound in DMSO. Plates were sealed with breathable membranes (Millipore Sigma Z763624) and incubated for 18-24 hours at 37°C with 5% CO2. The MIC was determined as the minimum concentration for which OD600 < 0.1, as measured using a SpectraMax M3 plate reader. For initial screening experiments, active compounds were determined as those for which OD600 < 0.15. [0390] For Neisseria gonorrhoeae, MICs were determined via broth microdilution when screening compounds, via agar dilution when confirming values for a given novel compound (e.g., NG1), or via ETEST when testing a standard-of-care antibiotic, per CLSI M100 and M07 guidelines. Prior to MIC testing, frozen stocks were passaged twice on chocolate agar plates (CAP; Hardy Diagnostics, H25). N. gonorrhoeae broth microdilution was performed by first preparing the bacterial inoculum by picking FIG.1 147 Docket No.: BI-11213-PCT individual colonies from an overnight CAP, suspending in PBS to OD6000.08, and diluting the suspension 1:200 in Graver Wade media61. Within 15 minutes of inoculum preparation, each well of a 96- or 384-well plate was inoculated with bacteria and compound (serially diluted in DMSO) such that the final DMSO concentration in each well was ≤1% and bacterial concentration was ~5 × 105 CFU/mL. Plates were incubated at 36-37°C with 5% CO2 for 20-24 hours. The MIC was determined as the concentration of compound resulting in complete inhibition of growth both visually and as measured by PrestoBlue HS Cell Viability Reagent (Invitrogen) after 1-2 hours of incubation. N. gonorrhoeae agar dilution was performed for novel compounds by first preparing agar dilution plates following CLSI M07 guidelines. Briefly, serial dilutions of 100× compound stock solutions were made in DMSO and added to molten agar, made of gonococcal (GC) medium base (BD Difco 228950) with 1% IsovitaleX Enrichment (BD 211876), which had been equilibrated to 45-50°C in a water bath. The agar and compound solution were mixed thoroughly and poured into a 6-well plate and allowed to solidify at room temperature. A DMSO-only growth control was included with every dilution series. Plates were used immediately or stored in sealed plastic bags at 4°C for up to a week and allowed to equilibrate to room temperature before use. The bacterial inoculum was prepared by making a 1:10 dilution of a 0.5 McFarland standardized inoculum of each bacterial strain in sterile saline and inoculating 2 μL of the suspension onto each marked location of a plate. The inoculated plates were allowed to dry and incubated at 36-37°C with 5% CO2 for 16-20 hours while inverted. MICs were read on a dark surface, with growth on the growth control plate required for validity. FIG.1 148 Docket No.: BI-11213-PCT [0391] Neisseria gonorrhoeae ETESTs (bioMerieux) were performed as described previously. Briefly, a sterile swab was soaked in a 0.5 McFarland standard bacterial suspension, excess fluid was removed, and the swab was used to evenly cover the entire surface of a plate of GC agar base with 1% IsoVitaleX. The plate was allowed to completely dry before placing an ETEST with sterile forceps, incubating for 18-24 hours at 37°C with 5% CO2, and reading the MIC as the lowest antibiotic concentration that inhibited growth. [0392] For M. tuberculosis, 100 μL of exponentially growing bacteria were seeded at a density of 5x104 per well in 7H9 supplemented with ADS (albumin dextrose saline), incubated with drug for 5 days at 37°C, then incubated for another 24 hours with 15 μL of 0.02% resazurin (w/v), and fluorescence was read with a SpectraMax M3 plate reader (Ex = 530 nm, Em = 590 nm). For other species not previously specified, an OD600 0.08 suspension was made in PBS and diluted 1:500 in fresh LB or Haemophilus Test Medium Broth (Remel) for Haemophilus. Each well of a 96-well plate received 99 μL of the bacterial suspension and 1 μL of compound. Plates were incubated at 37°C in ambient conditions, except for Haemophilus (5% CO2), for 18-24 hours and MICs were read visually and confirmed by measuring OD600 values. All assays were performed in biological duplicates. [0393] Bacterial time-kill assays. For MSSA and MRSA, cells were diluted 1:10,000 from an overnight culture into fresh LB and plated into 96-well flat-bottom clear plates using 99 μL working volumes. Plates were then sealed with breathable membranes, and cells were grown to early exponential phase, OD600 ~ 0.01 (corresponding to ~106 CFU/mL) in a 37°C incubator with shaking at 300 rpm. One μL of compound in two- FIG.1 149 Docket No.: BI-11213-PCT fold serial dilutions in DMSO was then added to each well to the final concentrations indicated, and bacterial cell cultures were sealed and re-incubated at 37°C with shaking at 300 rpm. At indicated times, cells were removed from incubation, serially diluted in room-temperature LB, and spotted on LB agar (Becton Dickinson 244520) in rectangular plates. Plated cells on LB agar were allowed to dry at room temperature before stationary incubation at 37°C overnight (18-24 hours). CFUs counts were manually determined. [0394] For N. gonorrhoeae, time-kill assays were performed as previously described. Specifically, a 0.5 McFarland suspension was prepared in sterile PBS using individual colonies picked from chocolate agar plates that had been grown for 18-20 hours at 37°C in a humid 5% CO2-enriched atmosphere. The suspension was diluted 1:500 in pre- warmed (37°C) GW media and 90 μL was added to each well in a round-bottom 96- well plate. The plate was pre-incubated for 4 hours with shaking at 150 rpm in a 35°C, 5% CO2-enriched incubator. At time 0, 10 μL of PBS (growth control) or antimicrobial (to achieve a final concentration of 0.5×, 1×, 2×, or 4×MIC, where the MIC of NG1 was 0.5 μg/mL and azithromycin MIC was 0.25 μg/mL) was added to each well of pre- incubated bacteria in duplicate, with a separate row for each time point. At indicated times, the corresponding row of cells was removed from incubation, serially diluted in PBS, and spotted on GC agar in rectangular plates. After drying at room temperature, plates were incubated overnight (18-24 hours) without shaking and CFU counts were manually determined. [0395] Cytotoxicity assay and IC50 determination. A resazurin-based assay, which quantifies the number of live cells in a sample, was used to monitor human cell viability FIG.1 150 Docket No.: BI-11213-PCT in the presence of a compound. Human cell lines were obtained from ATCC: HEK293 (CRL-1573), HepG2 (HB-8065), HSkMCs (PCS-950-010) and IMR-90 (CCL-186). HEK293 and HepG2 cells were grown to log phase in high-glucose Dulbecco’s Modified Eagle Medium (DMEM; Corning 10-013-CV) supplemented with 10% fetal bovine serum (FBS; ThermoFisher 16140071) and 1% penicillin843 streptomycin (ThermoFisher 15070063). HSkMCs were grown in mesenchymal stem cell basalmedium for adipose, umbilical and bone marrow-derived MSCs (ATCC: PCS- 500-030) supplemented with ATCC’s primary skeletal muscle growth kit (ATCC: PCS- 950-040) and 1% penicillin-streptomycin. IMR-90 cells were grown in in Eagle’s Minimum Essential Medium (EMEM; ATCC 30-2003) supplemented with 10% FBS and 1% penicillin-streptomycin. Cells were passaged < 5-10 times. For IC50 determination, 99 μL cells were plated into 96-well clear flat-bottom black tissue- culture-treated plates (Corning 3603) at a density of 104 cells/well and incubated at 37°C with 5% CO2. Twenty-four hours after plating, each well received one μL of two- fold serially-diluted test compound. Additional wells were treated with 1 μL of DMSO as a negative control and Triton X-100 (0.1% final concentration) as a positive control. Cells treated with the compound were re-incubated for 24 hours, after which 0.15 mM resazurin (Millipore Sigma R7017) was added to each well. After an additional 24 hours of incubation, the fluorescence was read at excitation/emission at 550/590 nm using a SpectraMax M3 plate reader. IC50 values were calculated by normalizing the fluorescence values based on the positive and negative controls and performing a nonlinear fit with the [Inhibitor] vs. response – Variable slope function in GraphPad Prism (v.10.1.0). HepG2 and HEK293 IC50 values for BRD-A99316759 and BRD- FIG.1 151 Docket No.: BI-11213-PCT A99906392 were determined as above, except in 384-well plates seeded with 4500 viable cells/well, where cells were treated with 1 μL (for HepG2) or 500 nL (for HEK293) of compound that were transferred using an acoustic dispenser (Labcyte Echo 555). All experiments were performed in biological duplicate. [0396] Spontaneous mutant generation and frequency of resistance experiments. S. aureus: S.aureus RN4220 was picked from single colonies and grown overnight in 2mL of fresh LB. OD600 was measured and the suspension was serially diluted and plated on solid agar (with no compound) to determine the initial inoculum. One mL of the same overnight culture (~109 CFU) was aliquoted and centrifuged at 3700 × g for 5 min. The cell pellet was resuspended to a final volume of 500 μL in fresh LB, then pipetted onto the surface of LB agar plates containing 1×, 2×, 4× or 8× agar MIC of SA1 (4 μg/mL). Cells were then spread using a bent, sterile inoculating loop, and plates were dried and inverted before stationary overnight incubation at 37°C. The next day, plates were removed from incubation, and colonies that grew on each plate were counted to calculate the frequency of resistance, which equals the total number of colonies counted divided by the total number of bacteria in the initial inoculum. [0397] N. gonorrhoeae: Isolated colonies of N. gonorrhoeae ATCC 49226 were picked from an overnight plate to make a heavy suspension in PBS. The suspension was serially diluted and plated on chocolate agar to determine the initial inoculum, and 500 μL of the suspension was added to each GC agar plate containing 0, 1×, 2×,4×, or 8× MIC of NG1. The suspension was spread and allowed to dry before stationary incubation at 37°C in a 5% CO2 incubator for 3 days. Colonies that emerged on each plate were individually picked and the elevated NG1 MIC was confirmed using both agar dilution FIG.1 152 Docket No.: BI-11213-PCT and broth microdilution methods in parallel with the parental strain for comparison. The frequency of resistance was calculated as the total number of colonies counted divided by the total number of bacteria inoculated on each plate. [0398] DiSC3(5) fluorescence. Individual colonies 883 of S. aureus RN4220 were picked and grown in 2 mL liquid LB overnight at 37°C with shaking at 300 rpm. Cells were diluted 1:100 from the overnight cultures into liquid LB and grown to mid-log phase, OD600 ~0.5, at 37°C with shaking at 300 rpm. For N. gonorrhoeae, multiple colonies from the overnight CAP were resuspended in prewarmed Graver Wade media to achieve OD600 ~0.5. DiSC3(5) (Invitrogen D306) was dissolved in DMSO and added to liquid cultures at a final concentration of 1 μM. After additional incubation in the presence of DiSC3(5) for 1 to 2 h, cells were plated in 200 μL working volumes in black, opaque flat-bottom 96-well plates, after which fluorescence was measured every 30 s for 5 minutes at an excitation/emission of 622/670 nm using a SpectraMax M3 plate reader. Cells were either untreated or treated with DMSO (1%), SA1, and NG1 at a final concentration of 10 μg/mL (10X MIC). Other control antibiotics were also tested at 10X MIC. Fluorescence was measured immediately following treatment according to the same specifications as above. [0399] pH-dependent growth inhibition: Individual colonies of MSSA and MRSA were picked and grown in 2 mL liquid LB overnight at 37°C with shaking at 300 rpm. Cells were then diluted 1:10,000 into fresh liquid LB titrated to pH 7.0, 8.0 and 9.0 using ammonium hydroxide (Millipore Sigma 09859). MIC values were determined as detailed above in MIC and bacterial growth inhibition assays. FIG.1 153 Docket No.: BI-11213-PCT [0400] Laurdan membrane fluidity assay: An OD600 of 0.5 cell suspension of N. gonorrhoeae ATCC 49226 was prepared in Graver Wade media. As previously described, a solution of 1 mM Laurdan (Sigma-Aldrich 40227) was prepared in 100% DMF (Sigma-Aldrich PHR1553) and stored in the dark at -20°C. Then, 100 μL of the 1 mM Laurdan stock was added to the cell suspension and incubated for 10 minutes at 37°C with shaking at 300 rpm while covered with aluminum foil. The cells were then centrifuged at 4,000 rpm for 5 minutes and washed three times in 10 mL of PBS with 0.2% (w/v) glucose. Cells were then resuspended in 10 mL of the same solution and distributed into a single 96-well opaque flat-bottom plate (Costar Black Polystyrene Plate, 266) with 100 μL per well and 198 μL in column 1. Two μL of NG1 or NG1 analog (i.e., NG2), starting at 128 μg/mL, was added to column 1, and serially diluted across columns 2-12 to obtain a final total volume of 100 μL in each well. To the control wells, Tween-20 (Sigma-Aldrich 655204), a known membrane fluidizer (Ipsen et al., 2022) starting at a concentration of 0.5% was added. Untreated or DMSO treated (1%) cells served as the negative control and Triclosan (starting at 62.5 μg/mL), and Azithromycin (starting at 250 μg/mL), were included as positive or neutral antibiotic controls. A kinetic read was taken every 45 seconds at 37°C using a SpectraMax M3 plate reader, exciting the plate at 330 nm and taking two emission readings at 460 nm and 500 nm. The Laurdan generalized polarization (GP) was calculated with the formula: GP = (I_460- I_500)/(I_460+ I_500), where I_460 indicates the fluorescence intensity at 460 nm and I_500 indicates the fluorescence intensity at 500 nm. All fluidity measurements were performed in biological duplicate. FIG.1 154 Docket No.: BI-11213-PCT [0401] NPN assay. Ten mL of an OD600 of 1 cell suspension of N. gonorrhoeae ATCC 49226 was prepared in Graver Wade media. As previously described, the cell suspension was spun at 4,000 rpm, 4°C for 15 minutes, washed twice in 5 mM HEPES buffer (Sigma-Aldrich SRE0065) with 20 mM glucose, and resuspended in an equal volume of the 20 μM NPN (Sigma-Aldrich 104043) in HEPES buffer. A 96-well opaque flat-bottom plate (Costar Black Polystyrene Plate, 10) was prepared with 100 μL of cells in 20 μM 926 NPN in HEPES buffer added to columns 2-12. In column 1, 198 μL of 20 μM NPN in HEPES buffer was added, followed by 2 μL of NG1 or NG1 analog (i.e., NG2) (starting concentration of 128 μg/mL). One-hundred μL from column 1 was serially diluted across columns 2-12 to obtain a final total volume of 100 μL in each well. DMSO (1%) treated cells served as the negative control. Plates were then incubated at room temperature for 1 hour with no shaking and the fluorescence at 355/420 nm (excitation/emission) was read using a SpectraMax M3 plate reader with readings taken from the top. All measurements were normalized to corresponding values from the untreated control and were performed in biological duplicates. [0402] SYTOX Green assay. Ten mL of an OD600 of 0.5 cell suspension of N. gonorrhoeae ATCC 49226 was prepared in Graver Wade media. 98 μL of cell suspension was added to a 96-well opaque flat-bottom plate (Costar Black Polystyrene Plate, 266), with 198 μL of cells to column 1. 2 μL of NG1 or NG2 (starting concentration of 128 μg/mL) was added to column 1 and 100 μL from column 1 was serially diluted across columns 2-12 to obtain a final total volume of 100 μL in each well. 1 μL of SYTOX Green Nucleic Acid Stain (5mM, S7020, Invitrogen, Carlsbad, CA), a DNA intercalating dye, was then added to each well at a final concentration of FIG.1 155 Docket No.: BI-11213-PCT 5 μM. DMSO (1%) treated cells served as the negative control, and Triton X-100 served as positive control, resulting in fully compromised membranes. At selected time points (0, 2 and 4 hours post-treatment), fluorescence at 504/523 nm (excitation/emission) was read with a SpectraMax M3 plate reader. All measurements were normalized to the untreated control and performed in biological duplicate. [0403] Checkerboard assays. The MICs of NG1, ceftriaxone, fosfomycin, and CCCP were determined to be 0.5, 0.008, 31.25, and 1 μg/mL, respectively, for ATCC 49226, and two-fold serial dilutions of each compound were tested from 10× to 0.156× MIC. The bacterial inoculum was made with a 1:100 dilution of an N. gonorrhoeae ATCC 49226 OD6000.08 suspension in Graver Wade media. Each well of a 96-well round- bottom clear plate (Corning 3799) received 99 μL of the suspension and one μL of two- fold serially diluted compound at 100× final concentration. The plates were incubated overnight at 37°C with 5% CO2 in a humidity-controlled incubator without shaking. After overnight incubation, OD600 was measured. Ten percent PrestoBlue™ Cell Viability Reagent (Invitrogen, A13261) was added to each well, to obtain quantitative cell viability measurements. Four hours post-incubation at 37°C, fluorescence was read at an excitation/emission of 550/590 nm using a SpectraMax M3 plate reader. MICs were determined as the minimum inhibitory concentration that leads to at least 50% growth inhibition (compared to the untreated control), and the fractional inhibitory concentration index (FICi) for drug combinations was determined. FICi was calculated as follows: FIG.1 Docket No.: BI-11213-PCT where MICA and MICB are the MIC of each antibiotic when administered individually. MICAB is the MIC of antibiotic A in combination with antibiotic B, and MICBA is the MIC of antibiotic B in combination with antibiotic A. FICi of < 0.5 indicates synergy, values between 0.5-4 indicate indifference, and > 4 indicates antagonism. For all combinations tested here, the FICi was 3, indicating indifference. [0404] Toxicity studies. Hemolysis and modified Ames genotoxicity studies were performed as described previously. All animal studies were performed at the Wyss Institute at Harvard in accordance with protocol IS00000852-6, approved by the Harvard Medical School Institutional Animal Care and Use Committee and the Committee on Microbiological Safety. To test the systemic toxicity of SA1, female C57BL/6J mice (6-12 weeks old, 22 ± 2 g, Jackson Laboratory) were given increasing doses of SA1, up to 80 mg/kg. To test the systemic toxicity of NG1, female BALB/c mice (6-8 weeks old, 20 ± 2 g, Jackson Laboratory) were given increasing doses of NG1, up to 100 mg/kg. Both compounds were formulated in a 10% compound in DMSO:45% PEG300:45% water solution and administered as a 200 μL intraperitoneal injection. Mice were observed for at least 24 hours for typical signs of toxicity, including impaired movement, lethality, and irritation. Results were representative of at least three mice per dose of each compound. [0405] Mouse S. aureus topical wound infection model. Female C57BL/6J mice (22 ± 2 g, Jackson Laboratory) were given at least 2 days to acclimate and then rendered neutropenic with cyclophosphamide (Cytoxan) on Day -5 (150 mg/kg, I.P.) and Day -1 (100 mg/kg (Day -1, I.P.). On Day 0, a fresh suspension of S. aureus BAA1556 was FIG.1 157 Docket No.: BI-11213-PCT prepared in tryptic soy broth and titered via serial dilution and plating. Mice were given buprenorphine for anesthesia and kept sedated under isoflurane vapors (3%) during the infection procedure. A ~1.5 cm2 patch of skin was prepared on each mouse’s dorsal surface by shaving the fur, sterilizing the underlying skin, abrading the skin until visibly damaged (reddening and glistening) but not bleeding, wiping again with an alcohol swab, and allowing the skin to dry completely. Five μL of the S. aureus suspension, corresponding to an inoculum of 3 × 10^4 CFU, was pipetted onto the skin to initiate the bacterial infection. Treatments were administered at 1, 4, 8, 16, 21, and 24 hours post infection by pipetting 40 μL of formulation topically onto the infected skin and allowing to dry. Treatments groups consisted of n = 6 mice receiving SA1 (1% final concentration, prepared as described above), n = 6 mice receiving vehicle control (DMSO:PEG300:water at 10%:45%:45%), and n = 6 mice receiving the fusidic acid positive control (0.25% final concentration in DMSO:PEG300:water at 10%:45%:45%) At 25 hours post-infection (~1 hour following the last topical treatment), all mice were euthanized by CO2 asphyxiation, and wounds were wiped with an alcohol pad, excised, weighed, and homogenized in 3 mL of sterile PBS using a Polytron PT10-35 with a 12 mm aggregate that was cleaned with ethanol and water between samples. Homogenized wounds were serially diluted and plated onto BHI agar to determine bacterial titers (CFU/g tissue). [0406] Mouse N. gonorrhoeae vaginal infection model. Ovariectomized female BALB/cJ mice (23 ± 3 g, Jackson Laboratory) were given over a week to acclimate prior to handling. As described previously, two days prior to infection (Day -2), vaginal lavage was performed for estrous staging and monitoring of the vaginal microbiota via FIG.1 158 Docket No.: BI-11213-PCT culture on MacConkey and Brain Heart Infusion agar plates. To increase susceptibility to infection, each mouse was injected with 17Β-estradiol (0.23 mg, I.P.) on Day -2 and Day 0. To reduce the overgrowth of commensal bacteria that occurs with estradiol treatment, mice were given streptomycin (1.2 mg, I.P.) and vancomycin (0.6 mg, I.P.) (1 dose on Day -2, two doses at least 5 hours apart on Day -1 and Day 0) as well as trimethoprim (0.4 g/L) in the drinking water (refreshed on Day 0). On Day 0, the inoculum was prepared by collecting isolated colonies of N. gonorrhoeae ATCC49226 from an overnight chocolate agar plate in sterile PBS to achieve an OD 0.2. Within one hour of preparation, the vagina was first rinsed with 30 μL of 50 mM HEPES (pH 7.4) and then 20 μL of the bacterial suspension (3 × 106 CFU per mouse) was pipetted intravaginally while the mouse was held by the tail with paws grasping the wire cage for at least 1 minute. Serial dilutions of the bacterial suspension were plated onto chocolate agar to determine the initial inoculum. Treatments were administered at 2, 6, 10, 18, and 24 hours after infection by pipetting 20 μL of test compound NG1 (1% final concentration in 10% DMSO, 45% PEG300, 45% water, n=9), ceftriaxone (0.1% w/v in water, n=5), or vehicle control (10% DMSO, 45% PEG300, 45% water, n=8) intravaginally; mice were suspended by the tail for 1 minute before being released into the cage. At 26 hours after infection, mice were euthanized by CO2 asphyxiation and vaginal lavage was performed using 60 μL of Graver Wade media with 0.05% saponin. N. gonorrhoeae burden was determined by plating 30 μL of neat lavage and 10-fold serial dilutions in PBS onto Thayer Martin Agar Improved (Thermo Fisher); colonies were counted after 24 hours of incubation at 37°C with 5% CO2. FIG.1 159 Docket No.: BI-11213-PCT [0407] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Example System and Device [0408] FIG.32 illustrates an example system generally at 3200 that includes an example computing device 3202 that is representative of one or more computing systems and/or devices that may implement the various techniques described herein. This is illustrated through inclusion of the data processor 108. The computing device 3202 may be, for example, a server of a service provider, a device associated with a client (e.g., a client device), an on-chip system, and/or any other suitable computing device or computing system. [0409] The example computing device 3202 as illustrated includes a processing device 3204, one or more computer-readable media 3206, and one or more I/O interfaces 3208 that are communicatively coupled, one to another. Although not shown, the computing device 3202 may further include a system bus or other data and command transfer system that couples the various components, one to another. A system bus can include any one or combination of different bus structures, such as a memory bus or memory FIG.1 160 Docket No.: BI-11213-PCT controller, a peripheral bus, a universal serial bus, and/or a processor or local bus that utilizes any of a variety of bus architectures. A variety of other examples are also contemplated, such as control and data lines. [0410] The processing device 3204 is representative of functionality to perform one or more operations using hardware. Accordingly, the processing device 3204 is illustrated as including hardware elements 3210 that may be configured as processors, functional blocks, and so forth. This may include implementation in hardware as an application specific integrated circuit or other logic device formed using one or more semiconductors. The hardware elements 3210 are not limited by the materials from which they are formed or the processing mechanisms employed therein. For example, processors may be comprised of semiconductor(s) and/or transistors (e.g., electronic integrated circuits (ICs)). In such a context, processor-executable instructions may be electronically executable instructions. [0411] The computer-readable storage media 3206 is illustrated as including memory/storage 3212. The memory/storage 3212 represents memory/storage capacity associated with one or more computer-readable media. The memory/storage 3212 may include volatile media (such as random-access memory (RAM)) and/or nonvolatile media (such as read only memory (ROM), Flash memory, optical disks, magnetic disks, and so forth). The memory/storage 3212 may include fixed media (e.g., RAM, ROM, a fixed hard drive, and so on) as well as removable media (e.g., flash memory, a removable hard drive, an optical disc, and so forth). The computer-readable media 3206 may be configured in a variety of other ways as further described below. FIG.1 161 Docket No.: BI-11213-PCT [0412] Input/output interface(s) 3208 are representative of functionality to allow a user to enter commands and information to computing device 3202, and also allow information to be presented to the user and/or other components or devices using various input/output devices. Examples of input devices include a keyboard, a cursor control device (e.g., a mouse), a microphone, a scanner, touch functionality (e.g., capacitive or other sensors that are configured to detect physical touch), a camera (e.g., which may employ visible or non-visible wavelengths such as infrared frequencies to recognize movement as gestures that do not involve touch), and so forth. Examples of output devices include a display device (e.g., a monitor or projector), speakers, a printer, a network card, tactile-response device, and so forth. Thus, the computing device 3202 may be configured in a variety of ways as further described below to support user interaction. [0413] Various techniques may be described herein in the general context of software, hardware elements, or program modules. Generally, such modules include routines, programs, objects, elements, components, data structures, and so forth that perform particular tasks or implement particular abstract data types. The terms “module,” “functionality,” and “component” as used herein generally represent software, firmware, hardware, or a combination thereof. The features of the techniques described herein are platform-independent, meaning that the techniques may be implemented on a variety of commercial computing platforms having a variety of processors. [0414] For instance, the terms “module,” “functionality,” and “component” may include a hardware and/or software system that operates to perform one or more functions. For example, a module, functionality, or component may include a computer processor, a FIG.1 162 Docket No.: BI-11213-PCT controller, or another logic-based device that performs operations based on instructions stored on a computer-readable storage medium, such as a computer memory. Optionally, the computer-readable storage medium may be tangible and non-transitory. Alternatively, a module, functionality, or component may include a hard-wired device that performs operations based on hard-wired logic of the device. Various modules, systems, and components shown in the attached figures may represent the hardware that operates based on software or hardwired instructions, the software that directs hardware to perform the operations, or a combination thereof. [0415] An implementation of the described modules and techniques may be stored on or transmitted across some form of computer-readable media. The computer-readable media may include a variety of media that may be accessed by the computing device 3202. By way of example, and not limitation, computer-readable media may include “computer-readable storage media” and “computer-readable signal media.” [0416] “Computer-readable storage media” may refer to media and/or devices that enable persistent and/or non-transitory storage of information in contrast to mere signal transmission, carrier waves, or signals per se. Thus, computer-readable storage media refers to non-signal bearing media. The computer-readable storage media includes hardware such as volatile and non-volatile, removable and non-removable media, and/or storage devices implemented in a method or technology suitable for storage of information such as computer readable instructions, data structures, program modules, logic elements/circuits, or other data. Examples of computer-readable storage media may include, but are not limited to, RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disks (DVD) or other optical storage, FIG.1 163 Docket No.: BI-11213-PCT hard disks, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or other storage device, tangible media, or article of manufacture suitable to store the desired information and which may be accessed by a computer. [0417] “Computer-readable signal media” may refer to a signal-bearing medium that is configured to transmit instructions to the hardware of the computing device 3202, such as via a network. Signal media typically may embody computer readable instructions, data structures, program modules, or other data in a modulated data signal, such as carrier waves, data signals, or other transport mechanism. Signal media also include any information delivery media. The term “modulated data signal” means a signal that has one or more of its characteristics set or changed in such a manner as to encode information in the signal. By way of example, and not limitation, communication media include wired media such as a wired network or direct-wired connection, and wireless media such as acoustic, RF, infrared, and other wireless media. [0418] As previously described, hardware elements 3210 and computer-readable media 3206 are representative of modules, programmable device logic and/or fixed device logic implemented in a hardware form that may be employed in some embodiments to implement at least some aspects of the techniques described herein, such as to perform one or more instructions. Hardware may include components of an integrated circuit or on-chip system, an application-specific integrated circuit (ASIC), a field-programmable gate array (FPGA), a complex programmable logic device (CPLD), and other implementations in silicon or other hardware. In this context, hardware may operate as a processing device that performs program tasks defined by instructions and/or logic FIG.1 164 Docket No.: BI-11213-PCT embodied by the hardware as well as a hardware utilized to store instructions for execution, e.g., the computer-readable storage media described previously. [0419] Combinations of the foregoing may also be employed to implement various techniques described herein. Accordingly, software, hardware, or executable modules may be implemented as one or more instructions and/or logic embodied on some form of computer-readable storage media and/or by one or more hardware elements 3210. The computing device 3202 may be configured to implement particular instructions and/or functions corresponding to the software and/or hardware modules. Accordingly, implementation of a module that is executable by the computing device 3202 as software may be achieved at least partially in hardware, e.g., through use of computer- readable storage media and/or hardware elements 3210 of the processing device 3204. The instructions and/or functions may be executable/operable by one or more articles of manufacture (for example, one or more computing devices 3202 and/or processing devices 3204) to implement techniques, modules, and examples described herein. [0420] The techniques described herein may be supported by various configurations of the computing device 3202 and are not limited to the specific examples of the techniques described herein. This functionality may also be implemented all or in part through use of a distributed system, such as over a “cloud” 3214 via a platform 3216 as described below. [0421] The cloud 3214 includes and/or is representative of a platform 3216 for resources 3218, which are depicted including the data processor 108. The platform 3216 abstracts underlying functionality of hardware (e.g., servers) and software resources of the cloud 3214. The resources 3218 may include applications and/or data FIG.1 165 Docket No.: BI-11213-PCT that can be utilized while computer processing is executed on servers that are remote from the computing device 3202. Resources 3218 can also include services provided over the Internet and/or through a subscriber network, such as a cellular or Wi-Fi network. [0422] The platform 3216 may abstract resources and functions to connect the computing device 3202 with other computing devices. The platform 3216 may also serve to abstract scaling of resources to provide a corresponding level of scale to encountered demand for the resources 3218 that are implemented via the platform 3216. Accordingly, in an interconnected device embodiment, implementation of functionality described herein may be distributed throughout the system 3200. For example, the functionality may be implemented in part on the computing device 3202 as well as via the platform 3216 that abstracts the functionality of the cloud 3214. References related to antimicrobial discovery include the following: 1) ChempropYang, K., Swanson, K., Jin, W., Coley, C., Eiden, P., Gao, H., Guzman-Perez, A., Hopper, T., Kelley, B., Mathea, M., et al. (2019). Analyzing learned molecular representations for property prediction. J. Chem. Inf. Model. 59, 3370–3388.10.1021/acs.jcim.9b00237. 2) Polishchuk, P. (2020). CReM: chemically reasonable mutations framework for structure generation. J. Cheminform.12, 28.10.1186/s13321-020-00431-w. 3) Jin, W., Barzilay, R., and Jaakkola, T. (2018). Junction Tree Variational Autoencoder for Molecular Graph Generation. arXiv. 10.48550/arxiv.1802.04364. FIG.1 166 Docket No.: BI-11213-PCT 4) Wong, F., Zheng, E.J., Valeri, J.A., Donghia, N.M., Anahtar, M.N., Omori, S., Li, A., Cubillos-Ruiz, A., Krishnan, A., Jin, W., et al. (2023). Discovery of a structural class of 1067 antibiotics with explainable deep learning. Nature. 10.1038/s41586-023-06887-8. 5) Anahtar, M.N. Machine learning-guided discovery of antibiotics for N. gonorrhoeae.(2023). 6) A. Gulati, A. Jorgenson, A. Junaid, D. E. Ingber, Modeling Healthy and Dysbiotic Vaginal Microenvironments in a Human Vagina-on-a-Chip. Journal of visualized experiments : JoVE, (2024). All of which are incorporated herein by reference for all purposes. [0423] Features described above as well as those claimed below may be combined in various ways without departing from the scope thereof. The following examples illustrate some possible, non-limiting combinations: [0424] (A1) A method of identifying or creating one or more compounds having antimicrobial activity, the method comprising: screening a library of initial chemical substructures to identify at least one active chemical substructure from the initial chemical substructures, the screening of the library of initial chemical substructures being performed by a substructure screening module, wherein the substructure screening module predicts the activity of the active chemical substructure against a target microbe; providing the at least one active chemical substructure to a generative module to create a plurality of candidate compounds; screening the plurality of candidate compounds to identify a target set of compounds, the screening of the plurality of candidate compounds being performed by a compound screening module; FIG.1 167 Docket No.: BI-11213-PCT and optionally testing the target set of compounds to determine the activity of the target set of compounds against the target microbe, the target set of compounds being a subset of the plurality of candidate compounds, and the target set of compounds having the active chemical substructure. [0425] (A2) For the method denoted as (A1) the generative module is selected from a genetic generative module, a fragment generative module, or both. [0426] For example, the fragment generative module may comprise a fragment-based variational autoencoder as described above and /or as depicted in Fig.16. [0427] (A3) For the method denoted as (A1) or (A2) the screening of the library of initial chemical substructures includes training the substructure screening module to identify which of the chemical substructures has greater potential to exhibit antimicrobial activity against the target microbe. [0428] (A4) For the method denoted as (A1), (A2), or (A3) the substructure screening module is a machine learning module. [0429] (A5) For the method denoted as (A4) the machine learning module includes one or more graph neural networks (GNNs) representing a deep learning model that infers molecular properties by representing chemical structures as mathematical graphs. [0430] (A6) For the method denoted as (A4) or (A5) the machine learning module uses message passing operations to assign values to nodes and/or edges of mathematical graphs and update those values iteratively based upon training of the machine learning module. [0431] (A7) For the method denoted as (A4), (A5), or (A6) the machine learning module produces a single output value for each chemical substructure of between 0 and 1, FIG.1 168 Docket No.: BI-11213-PCT representing a probability that each chemical substructure of the library of chemical substructures possesses antimicrobial activity against the target microbes. [0432] (A8) For the method denoted as any of (A1) through (A7) the library of initial chemical substructures typically, e.g. may, include at least 100,000 but not greater than 10 billion substructures. [0433] (A9) For the method denoted as any of (A1) through (A8), the screening of the library of initial substructures may include removing initial substructures of the library of initial substructures, wherein the initial substructures exhibit one or more of: 1) predicted cytotoxicity above a threshold; 2) PAINS or Brenk substructures; or 3) structural similarity to compounds that exhibit activity against the target microbe. [0434] By removing these initial substructures, substructures with undesirable chemical attributes can be removed. The method therefore makes better use of computer resources by only focusing further processing on substructures which are more likely to yield positive and useful results. [0435] (A10) For the method denoted as any of (A1) through (A9) the at least one active chemical substructure is provided to the generative module and the generative module includes an algorithm that provides a computational framework that starts with at least one active chemical substructure and generates the candidate compounds by adding, replacing, or deleting atoms and functional groups. [0436] (A11) For the method denoted as any of (A1) through (A10) the at least one active chemical substructure is provided to the generative module, which is based on a generative deep learning system. FIG.1 169 Docket No.: BI-11213-PCT [0437] (A12) For the method denoted as any of (A1) through (A11) the generative module includes a fragment-based variational autoencoder (FVAE), optionally trained on a library of 10,000 to 1 billion compounds. [0438] (A13) For the method denoted as any of (A1) through (A12) the generative module employs a set of atoms that include C, N, O, Cl, or any combination thereof to create all or a subset of chemically possible and/or stable substructures having a preselected number (e.g., at least 8, 9, 10 or more, but no greater than 25, 19, 18 or less) of such atoms, the chemically possible substructures being bonded to the at least one active chemical substructure. [0439] (A14) For the method denoted as (A13) the set of atoms includes at least two of F, Br, or S. [0440] The methods denoted above as (A1) through (A13) may be computer- implemented methods, or may be partially implemented by a computer. [0441] (B1) A system comprising a processor, a computer readable medium, and a combination of any or all of the modules of the methods denoted as any of (A1) through (A14), wherein the processor, the computer readable medium, and the modules are configured to cooperatively carry out the steps of the method denoted as any of (A1) through (A14). [0442] (B2) For example, the system denoted as (B1) above may comprise a processor and a computer-readable / machine-readable medium comprising instructions which, when implemented by the processor, cause the processor to perform any of the methods described herein, including the methods denoted as any of (A1) through (A14), with or without a step of testing the target set of compounds. The testing may be carried out FIG.1 170 Docket No.: BI-11213-PCT separately, for example in a laboratory, in the manner described above in the application. [0443] (B3) The system denoted as (B1) or (B2) may comprise, for example, a substructure screening module configured to screen a library of initial chemical substructures to identify at least one active chemical substructure from the initial chemical substructures; wherein the substructure screening module predicts the activity of the active chemical substructure against a target microbe; a generative module configured to receive the at least one active chemical substructure and create a plurality of candidate compounds; and a compound screening module configured to screen the plurality of candidate compounds to identify a target set of compounds. [0444] (B4) The system denoted as (B1) through (B3) may enable the target set of compounds to be tested to determine the activity of the target set of compounds against the target microbe, the target set of compounds being a subset of the plurality of candidate compounds, and the target set of compounds having the active chemical substructure. [0445] (B5) The present application also discloses a computer-readable / machine- readable medium comprising instructions which, when implemented by a processor, cause the processor to perform any of the methods described herein, including the methods denoted as any of (A1) through (A14), with or without a step of testing the target set of compounds. [0446] (C1) A pharmaceutical composition for treating or preventing a microbial infection in a subject comprising: a compound of structure VI as follows: FIG.1 171 Docket No.: BI-11213-PCT
R1 is independently selected from H, halogen, or C1-C2 alkyl; R2 is independently selected from H or halogen; R3 is independently selected from H or halogen; R4 is independently selected from H or C1-C2 alkyl; R5 is independently selected from H, or halogen; R6 is independently selected from H, alkoxy or halogen; and A- is an anion; or a pharmaceutically acceptable salt and/or stereoisomer thereof. [0447] (C2) The pharmaceutical composition of (C1), wherein the microbial infection is caused at least in part by Neisseria gonorrhoeae. [0448] (C3) The pharmaceutical composition of (C1) or (C2), wherein the compound of structure VI is defined by at least two or any possible combination of the following: 1) FIG.1 172 Docket No.: BI-11213-PCT R1 is methyl or Cl; 2) R2 is Cl; 3) R3 is Cl or F; 4) R4 is methyl; 5) R5 is Cl; 6) R6 is methoxy or Cl; 7) R7 is methyl; 8) R1 is H; 9) R2 is H; 10) R3 is H; 11) R4 is H; 12) R5 is H; 13) R6 is H; and/or 14) R7 is H. [0449] (C4) The pharmaceutical composition of (C1), (C2) or (C3), wherein R5 is Cl and R6 is methoxy or Cl. [0450] (C5) The pharmaceutical composition of (C1), (C2) or (C3), wherein the compound of structure VI is selected from at least one of the following: [(3,4-dichlorophenyl)methyl]-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; FIG.1 173 Docket No.: BI-11213-PCT
yl)-1-[(2-methylphenyl)methyl]-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; - chlorophenyl)methyl]-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; FIG.1 174 Docket No.: BI-11213-PCT
yl)methyl]-3-(4-methoxyphenyl)-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; -3-(3,4-dichlorophenyl)-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; FIG.1 175 Docket No.: BI-11213-PCT
[(4-fluorophenyl)methyl]-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; and/or -3-phenyl-6,7-dihydro-5H-pyrrolo[1,2- a]imidazol-1-ium;chloride. FIG.1 176 Docket No.: BI-11213-PCT [0451] (C6) The pharmaceutical composition of any one of (C1)-(C5), wherein the microbial infection is resistant to one or more antimicrobial agents. [0452] (C7) The pharmaceutical composition of (C6), wherein the one or more antimicrobial agents are selected from amoxicillin, ampicillin, nafcillin, piperacillin, or penicillin G. [0453] (C8) The pharmaceutical composition of any one of (C1)-(C7), further comprising a pharmaceutically acceptable carrier, the pharmaceutical carrier combined with a therapeutically effective amount of the compound to form a solid, gel, suspension, or liquid dosage form. [0454] (C9) The pharmaceutical composition of any one of (C1)-(C8), wherein the composition is provided in a dosage form that contains from about 0.001 mg/kg to about 1000 mg/kg of the compound. [0455] (10) The pharmaceutical composition of any one of (C1)-(C9), wherein the compound of structure VI is between 0.1% and 50% (w/w) of the composition. [0456] (C11) A pharmaceutical composition for treating or preventing a microbial infection in a subject comprising: a compound of structure VII as follows: FIG.1 177 Docket No.: BI-11213-PCT
R1 is independently selected from H or halogen; R2 is independently selected from H or C1-C2 alkyl; R3 is independently selected from H or OH; R4 is independently selected from H or OH; and R5 is independently selected from H, OH or alkoxy. [0457] (C12) The pharmaceutical composition of (C11), wherein the microbial infection is caused at least in part by Neisseria gonorrhoeae. [0458] (C13) The pharmaceutical composition of (C11) or (C12), wherein the compound of structure VII is defined by at least two or any possible combination of the following: 1) R1 is Br; 2) R2 is methyl; 3) R3 is OH; 4) R4 is OH; 5) R5 is OH; 6) R5 is methoxy; 7) R1 is H; 8) R2 is H; 9) R3 is H; 10) R4 is H; and/or 11) R5 is H. FIG.1 178 Docket No.: BI-11213-PCT [0459] (C14) The pharmaceutical composition of (C11), (C12) or (C13), wherein at least two or all three of R3-R5 are OH. [0460] (C15) The pharmaceutical composition of (C11), (C12) or (C13), wherein the compound of structure VII is selected from at least one of the following: benzene-1,2,3-triol; FIG.1 179 Docket No.: BI-11213-PCT
FIG.1 180 Docket No.: BI-11213-PCT [0461] (C16) The pharmaceutical composition of any one of (C11)-(C15), wherein the microbial infection is resistant to one or more antimicrobial agents. [0462] (C17) The pharmaceutical composition of (C16), wherein the one or more antimicrobial agents are selected from amoxicillin, ampicillin, nafcillin, piperacillin, or penicillin G. [0463] (C18) The pharmaceutical composition of any one of (C11)-(C17), further comprising a pharmaceutically acceptable carrier, the pharmaceutical carrier combined with a therapeutically effective amount of the compound to form a solid, gel, suspension, or liquid dosage form. [0464] (C19) The pharmaceutical composition of any one of (C11)-(C18), wherein the composition is provided in a dosage form that contains from about 0.001 mg/kg to about 1000 mg/kg of the compound. [0465] (C20) The pharmaceutical composition of any one of (C11)-(C19), wherein the compound of structure VII is between 0.1% and 50% (w/w) of the composition. [0466] Conclusion [0467] Although the invention has been described in language specific to structural features and/or methodological acts, it is to be understood that the invention defined in the appended claims is not necessarily limited to the specific features or acts described. Rather, the specific features and acts are disclosed as example forms of implementing the claimed invention. FIG.1 181 Docket No.: BI-11213-PCT

Claims

CLAIMS What is claimed is: 1. A pharmaceutical composition comprising: (i) a compound of substructure II bonded to substructure Y1 as follows: Substructure II O Y1 wherein: R1 – R5 are independently selected from C or N with at least three, more typically at least four, and quite possibly all five of R1 - R5 being C; R1A – R5A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, OH or halogen, with R1A – R5A only being nothing if, respectively, R1 – R5 is selected as N; and substructure Y1 is: (a) FIG.1 182 Docket No.: BI-11213-PCT R12 O R10 R6 – R10 are independently selected from H, CH3, and halogen with no more than one of R6 – R10 being CH3, no more than three, and more typically no more than two of R6 – R10 being halogen, and at least two, and more typically at least three of R6 – R10 being H; R11 is selected from CH2, or C2-C4 alkyl or alkylene, and is typically C2H4; and R12 is selected from H, CH3, or C2-C4 alkyl or alkylene, and is typically CH3; or (b) R10 wherein: FIG.1 183 Docket No.: BI-11213-PCT R6 – R9 are independently selected from C or N, with typically at least one, two, or three of R6 – R9 being N, and one or two of R6 – R9 being C; and R10 is independently selected from H, CH3, or CH2CH3 and is bonded to one of R6 – R9, which has been independently selected as N; or (ii) a compound of structure VI as follows: R1 is independently selected from H, halogen, or C1-C2 alkyl; R2 is independently selected from H or halogen; R3 is independently selected from H or halogen; R4 is independently selected from H or C1-C2 alkyl; R5 is independently selected from H, or halogen; R6 is independently selected from H, alkoxy or halogen; and A- is an anion; or FIG.1 184 Docket No.: BI-11213-PCT (iii) a compound of structure VII as follows: R1 is independently selected from H or halogen; R2 is independently selected from H or C1-C2 alkyl; R3 is independently selected from H or OH; R4 is independently selected from H or OH; and R5 is independently selected from H, OH or alkoxy; or (iv) a compound of substructure I bonded to Z1 and substructure Z2 as follows: FIG.1 185 Docket No.: BI-11213-PCT R1A H wherein: R1 – R4 are independently selected from C or N with at least two, more typically at least three, and quite possibly all four of R1 - R4 being C; R5 – R9 are independently selected from C or N with at least three, more typically at least four, and quite possibly all five of R5 - R9 being C; R1A – R4A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, OH or halogen, with R1A – R4A only being nothing where, respectively, R1 – R4 is selected as N; and R5A – R9A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, OH, or halogen, with R5A – R9A only being nothing if, respectively, R5 – R9 is selected as N; Z1 is H or CH3; and Z2 is a substructure as follows: FIG.1 186 Docket No.: BI-11213-PCT R11A R12A R10 is selected from CH2, NH, S or O, but is typically either S or O; R11 – R15 are independently selected from C or N, with no more than two of R11 – R15 more typically no more than one of R11 – R15 being N; R11A – R15A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, carboxyl, OH or halogen, with R11A – R15A only being nothing if, respectively, R11 – R15 is selected as N; at least one of R11A – R15A is carboxyl; and at least two of R11A – R15A are H; or (iv) a compound of substructure II bonded to substructure Y1 as follows: FIG.1 187 Docket No.: BI-11213-PCT Substructure II O Y1 wherein: R1 – R5 are independently selected from C or N with at least three, more typically at least four, and quite possibly all five of R1 - R5 being C; R1A – R5A are independently selected from nothing, H, CH3, substituted or unsubstituted C2 – C4 alkyl or alkylene, OH or halogen, with R1A – R5A only being nothing if, respectively, R1 – R5 is selected as N; and substructure Y1 is: (a) FIG.1 188 Docket No.: BI-11213-PCT R12 O R10 R6 – R10 are independently selected from H, CH3, and halogen with no more than one of R6 – R10 being CH3, no more than three, and more typically no more than two of R6 – R10 being halogen, and at least two, and more typically at least three of R6 – R10 being H; R11 is selected from CH2, or C2-C4 alkyl or alkylene, and is typically C2H4; and R12 is selected from H, CH3, or C2-C4 alkyl or alkylene, and is typically CH3; or (b) R10 wherein: FIG.1 189 Docket No.: BI-11213-PCT R6 – R9 are independently selected from C or N, with typically at least one, two, or three of R6 – R9 being N, and one or two of R6 – R9 being C; and R10 is independently selected from H, CH3, or CH2CH3 and is bonded to one of R6 – R9, which has been independently selected as N; or (v) a compound III as shown below: - - - hydroxy-3,4,6,6a,8,9,10,10a-octahydro-2H-pyrano[2,3-c][1,5]oxazocine-1- carboxamide; or (vi) a compound of structure IV as shown below: FIG.1 190 Docket No.: BI-11213-PCT
R1 and R2 are independently selected from H, alkoxy, halogen, or a combination thereof; or (vii) a compound of structure V as shown below: FIG.1 191 Docket No.: BI-11213-PCT wherein: R1, R2, R3, R4, and R5 are independently selected from H, halogen, or trifluoromethyl, with at least three, possibly four or all of R1, R2, R3, R4, and R5 being H, no more than two of R1, R2, R3, R4, and R5 being halogen, and/or no more than one of R1, R2, R3, R4, and R5 being trifluoromethyl; or a pharmaceutically acceptable salt and/or stereoisomer thereof.
2. The pharmaceutical composition of claim 1, wherein the composition comprises: a compound of structure VI as follows: R1 is independently selected from H, halogen, or C1-C2 alkyl; R2 is independently selected from H or halogen; R3 is independently selected from H or halogen; FIG.1 192 Docket No.: BI-11213-PCT R4 is independently selected from H or C1-C2 alkyl; R5 is independently selected from H, or halogen; R6 is independently selected from H, alkoxy or halogen; and A- is an anion.
3. The pharmaceutical composition of claim 2, wherein the compound of structure VI is defined by at least two or any possible combination of the following: 1) R1 is methyl or Cl; 2) R2 is Cl; 3) R3 is Cl or F; 4) R4 is methyl; 5) R5 is Cl; 6) R6 is methoxy or Cl; 7) R7 is methyl; 8) R1 is H; 9) R2 is H; 10) R3 is H; 11) R4 is H; 12) R5 is H; 13) R6 is H; and/or 14) R7 is H.
4. The pharmaceutical composition of claim 2 or 3, wherein: (a) R1 is H, methyl or Cl, R2 is Cl or H, R3 is Cl, F or H and R4 is H or methyl, wherein at least one of R1-R4 is not H, optionally wherein one or two of R1-R4 is not H; and/or (b) R5 is H or Cl and R6 is Cl or methoxy, optionally wherein R5 is H or Cl and R6 is Cl or R5 is H and R6 is methoxy.
5. The pharmaceutical composition of claim 2, 3, or 4, wherein R5 is Cl and R6 is methoxy or Cl.
6. The pharmaceutical composition of claim 2, 3, or 4, wherein the compound of structure VI is selected from at least one of the following: FIG.1 193 Docket No.: BI-11213-PCT
NG10: 3-(4-chlor , ethyl]-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; NG11: 3-(3,4- - -6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; FIG.1 194 Docket No.: BI-11213-PCT
NG12: 3-(4-chlo p y p y y -6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; NG13: 1-[(3,4- - -6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; FIG.1 195 Docket No.: BI-11213-PCT
NG14: 1-[(2-chlor , enyl)-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; NG15: 3-(3,4-dichlorophenyl)-1-[(4-fluorophenyl)methyl]-6,7-dihydro-5H- pyrrolo[1,2-a]imidazol-1-ium;chloride; and/or FIG.1 196 Docket No.: BI-11213-PCT
NG16: 1-[(3-m dro-5H-pyrrolo[1,2- a]imidazol-1-ium;chloride.
7. The pharmaceutical composition of claim 1, wherein the composition comprises: a compound of structure VII as follows: FIG.1 197 Docket No.: BI-11213-PCT
R1 is independently selected from H or halogen; R2 is independently selected from H or C1-C2 alkyl; R3 is independently selected from H or OH; R4 is independently selected from H or OH; and R5 is independently selected from H, OH or alkoxy.
8. The pharmaceutical composition of claim 7, wherein the compound of structure VII is defined by at least two or any possible combination of the following: 1) R1 is Br; 2) R2 is methyl; 3) R3 is OH; 4) R4 is OH; 5) R5 is OH; 6) R5 is methoxy; 7) R1 is H; 8) R2 is H; 9) R3 is H; 10) R4 is H; and/or 11) R5 is H. FIG.1 198 Docket No.: BI-11213-PCT
9. The pharmaceutical composition of claim 7 or 8, wherein R1 is H or Br, R2 is H or methyl, R3 is OH, R4 is H or OH and R5 is OH or methoxy.
10. The pharmaceutical composition of claim 7, 8 or 9, wherein at least two or all three of R3-R5 are OH.
11. The pharmaceutical composition of claim 7, 8 or 9, wherein the compound of structure VII is selected from at least one of the following: NG19: 4-(4- FIG.1 199 Docket No.: BI-11213-PCT
NG20: 1,3-diol; and/or NG21: 5-methoxy-2-(5-methyl-4-phenoxy-1H-pyrazol-3-yl)phenol. FIG.1 200 Docket No.: BI-11213-PCT
12. The pharmaceutical composition of any one of the preceding claims, further comprising a pharmaceutically acceptable carrier, the pharmaceutical carrier combined with a therapeutically effective amount of the compound to form a solid, gel, suspension, or liquid dosage form, optionally wherein: (a) the composition is provided in a dosage form that contains from about 0.001 mg/kg to about 1000 mg/kg of the compound; and/or(b) the compound is between 0.1% and 50% (w/w) of the composition.
13. A compound of structure VI, a compound of structure VII, a compound of substructure I bonded to Z1 and substructure Z2, a compound of substructure II bonded to substructure Y1, compound III, or a compound of structure IV as defined in any of claims 1 to 11, for use in treating or preventing a microbial infection in a subject.
14. A pharmaceutical composition of any one of claims 1-12 for use in treating or preventing a microbial infection in a subject.
15. The compound for use of claim 13 or the composition for use of claim 14, wherein the compound is a compound of structure VI or structure VII as defined in any one of claims 2 to 11 and: (a) the microbial infection is caused at least in part by Neisseria gonorrhoeae; and/or FIG.1 201 Docket No.: BI-11213-PCT (b) the microbial infection is resistant to one or more antimicrobial agents, optionally wherein the one or more antimicrobial agents are selected from amoxicillin, ampicillin, nafcillin, piperacillin, or penicillin G.
16. A method of identifying or creating one or more compounds having antimicrobial activity, the method comprising: screening a library of initial chemical substructures to identify at least one active chemical substructure from the initial chemical substructures, the screening of the library of initial chemical substructures being performed by a substructure screening module, wherein the substructure screening module predicts the activity of the active chemical substructure against a target microbe; providing the at least one active chemical substructure to a generative module to create a plurality of candidate compounds; screening the plurality of candidate compounds to identify a target set of compounds, the screening of the plurality of candidate compounds being performed by a compound screening module; and optionally testing the target set of compounds to determine the activity of the target set of compounds against the target microbe, the target set of compounds being a subset of the plurality of candidate compounds, and the target set of compounds having the active chemical substructure.
17. The method described in claim 16, wherein the generative module is selected from a genetic generative module, a fragment generative module, or both. FIG.1 202 Docket No.: BI-11213-PCT
18. The method described in claim 17, wherein the fragment generative module comprises a fragment-based variational autoencoder.
19. The method described in any one of claims 16-18, wherein the screening of the library of initial chemical substructures includes training the substructure screening module to identify which of the chemical substructures has greater potential to exhibit antimicrobial activity against the target microbe.
20. The method described in any one of claims 16-19, wherein the substructure screening module is a machine learning module.
21. The method described in claim 20, wherein the machine learning module includes one or more graph neural networks (GNNs) representing a deep learning model that infers molecular properties by representing chemical structures as mathematical graphs.
22. The method described in claim 20 or 21, wherein the machine learning module uses message passing operations to assign values to nodes and/or edges of mathematical graphs and update those values iteratively based upon training of the machine learning module. FIG.1 203 Docket No.: BI-11213-PCT
23. The method as described in claim 20, 21, or 22, wherein the machine learning module produces a single output value for each chemical substructure of between 0 and 1, representing a probability that each chemical substructure of the library of chemical substructures possesses antimicrobial activity against the target microbes.
24. The method as described in any one of claims 16-23, wherein the library of initial chemical substructures includes at least 100,000 but not greater than 10 billion substructures.
25. The method as described in any one of claims 16-24, wherein the screening of the library of initial substructures may include removing initial substructures of the library of initial substructures, wherein the initial substructures exhibit one or more of: 1) predicted cytotoxicity above a threshold; 2) PAINS or Brenk substructures; or 3) structural similarity to compounds that exhibit activity against the target microbe.
26. The method as described in any one of claims 16-25, wherein the at least one active chemical substructure is provided to the generative module and the generative module includes an algorithm that provides a computational framework that starts with at least one active chemical substructure and generates the candidate compounds by adding, replacing, or deleting atoms and functional groups. FIG.1 204 Docket No.: BI-11213-PCT
27. The method as described in any one of claims 16-26, wherein the at least one active chemical substructure is provided to the generative module, which is based on a generative deep learning system.
28. The method as described in any one of the claims 16-27, wherein the generative module includes a fragment-based variational autoencoder (FVAE), optionally trained on a library of 10,000 to 1 billion compounds.
29. The method as described in any one of the claims 16-27, wherein the generative module employs a set of atoms that include C, N, O, Cl, or any combination thereof to create all or a subset of chemically possible and/or stable substructures having a preselected number (e.g., at least 8, 9, 10 or more, but no greater than 25, 19, 18 or less) of such atoms, the chemically possible substructures being bonded to the at least one active chemical substructure.
30. The method as described in claim 29, wherein, the set of atoms includes at least two of F, Br, or S.
31. A system comprising a processor, a computer readable medium, and a combination of any or all of the modules of the methods of claims 1 through 30, wherein the processor, the computer readable medium, and the modules are configured to cooperatively carry out the steps of the methods of claims 1 through 30. FIG.1 205 Docket No.: BI-11213-PCT
32. The system as described in claim 31, wherein the computer readable medium comprising instructions which, when implemented by the processor, causes the processor to perform any of the methods described herein, including the methods of any of claims 1 through 30, with or without a step of testing the target set of compounds.
33. The system as described in claim 31 or 32, wherein, for example, the substructure screening module configured to screen the library of initial chemical substructures to identify the at least one active chemical substructure from the initial chemical substructures; wherein the substructure screening module predicts the activity of the active chemical substructure against a target microbe; the generative module configured to receive the at least one active chemical substructure and create the plurality of candidate compounds; and the compound screening module configured to screen the plurality of candidate compounds to identify the target set of compounds.
34. The system as described in claim 31, 32, or 33, wherein the target set of compounds is enabled to be tested to determine the activity of the target set of compounds against the target microbe, the target set of compounds being a subset of the plurality of candidate compounds, and the target set of compounds having the active chemical substructure. FIG.1 206 Docket No.: BI-11213-PCT
PCT/US2025/023053 2024-04-05 2025-04-03 Antimicrobials and discovery thereof Pending WO2025212960A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202463575603P 2024-04-05 2024-04-05
US63/575,603 2024-04-05
US202463683242P 2024-08-14 2024-08-14
US63/683,242 2024-08-14

Publications (1)

Publication Number Publication Date
WO2025212960A1 true WO2025212960A1 (en) 2025-10-09

Family

ID=95450255

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/023053 Pending WO2025212960A1 (en) 2024-04-05 2025-04-03 Antimicrobials and discovery thereof

Country Status (1)

Country Link
WO (1) WO2025212960A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4657760A (en) 1979-03-20 1987-04-14 Ortho Pharmaceutical Corporation Methods and compositions using monoclonal antibody to human T cells
US5206344A (en) 1985-06-26 1993-04-27 Cetus Oncology Corporation Interleukin-2 muteins and polymer conjugation thereof
US5225212A (en) 1989-10-20 1993-07-06 Liposome Technology, Inc. Microreservoir liposome composition and method
JP2005225787A (en) * 2004-02-12 2005-08-25 Nippon Kayaku Co Ltd Hsp90 inhibitor
WO2014024056A1 (en) * 2012-08-06 2014-02-13 Daiichi Sankyo Company, Limited Pyrrolidine derivatives with antibacterial properties

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4657760A (en) 1979-03-20 1987-04-14 Ortho Pharmaceutical Corporation Methods and compositions using monoclonal antibody to human T cells
US5206344A (en) 1985-06-26 1993-04-27 Cetus Oncology Corporation Interleukin-2 muteins and polymer conjugation thereof
US5225212A (en) 1989-10-20 1993-07-06 Liposome Technology, Inc. Microreservoir liposome composition and method
JP2005225787A (en) * 2004-02-12 2005-08-25 Nippon Kayaku Co Ltd Hsp90 inhibitor
WO2014024056A1 (en) * 2012-08-06 2014-02-13 Daiichi Sankyo Company, Limited Pyrrolidine derivatives with antibacterial properties

Non-Patent Citations (23)

* Cited by examiner, † Cited by third party
Title
A. GULATIA. JORGENSONA. JUNAIDD. E. INGBER: "Modeling Healthy and Dysbiotic Vaginal Microenvironments in a Human Vagina-on-a-Chip", JOURNAL, 2024
ANAHTAR, M.N: "Machine learning-guided discovery of antibiotics for N", GONORRHOEAE, 2023
AUSUBEL ET AL.: "Current Protocols in Molecular Biology", 1992, JOHN WILEY & SONS
B. PERBAL: "A Practical Guide To Molecular Cloning", 1984
BAYAR IREM ET AL: "Antibacterial Activities of Imidazole-Based Compounds (A Review)", RUSSIAN JOURNAL OF ORGANIC CHEMISTRY (TRANSLATION OF ZHURNAL ORGANICHESKOI KHIMII), vol. 59, no. S1, 1 December 2023 (2023-12-01), Moscow, pages S7 - S19, XP093289674, ISSN: 1070-4280, Retrieved from the Internet <URL:https://link.springer.com/article/10.1134/S107042802313002X/fulltext.html> DOI: 10.1134/S107042802313002X *
CHEMPROPYANG, KSWANSON, KJIN, WCOLEY, CEIDEN, PGAO, HGUZMAN-PEREZ, AHOPPER, TKELLEY, BMATHEA, M ET AL.: "Analyzing learned molecular representations for property prediction", J. CHEM. INF. MODEL, vol. 59, 2019, pages 3370 - 3388
COHEN ET AL., CELL HOST & MICROBE, vol. 13, pages 632 - 642
GLOVER: "Remington's Pharmaceutical Sciences", 1985, MACE PUBLISHING COMPANY
HARLOWLANE: "Essential Immunology", 1988, COLD SPRING HARBOR LABORATORY PRESS
HOGAN ET AL.: "Handbook Of Experimental Immunology", vol. I-IV, 1986, COLD SPRING HARBOR LABORATORY PRESS
JAKOBYPASTAN: "Nucleic Acid Hybridization", 1979
JIN, WBARZILAY, RJAAKKOLA, T: "Junction Tree Variational Autoencoder for Molecular Graph Generation", ARXIV. 10.48550/ARXIV.1802.04364, 2018
LANGER, SCIENCE, vol. 249, 1990, pages 1527 - 1533
LI WEN-XING ET AL: "Screening of antibacterial compounds with novel structure from the FDA approved drugs using machine learning methods", AGING, vol. 14, no. 3, 12 February 2022 (2022-02-12), pages 1448 - 1472, XP093290635, ISSN: 1945-4589, Retrieved from the Internet <URL:https://pmc.ncbi.nlm.nih.gov/articles/PMC8876917/pdf/aging-14-203887.pdf> DOI: 10.18632/aging.203887 *
LIU SHUAI-SHUAI ET AL: "Novel spiro[chromanone-2,4'-piperidine]-4-one derivatives as potential inhibitors of fatty acid synthesis in pathogens: Design, synthesis, and biological evaluation", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER MASSON, AMSTERDAM, NL, vol. 250, 19 February 2023 (2023-02-19), XP087285846, ISSN: 0223-5234, [retrieved on 20230219], DOI: 10.1016/J.EJMECH.2023.115215 *
MORDENTI, JCHAPPELL, W ET AL.: "Toxicokinetics and New Drug Development", 1989, PERGAMON PRESS, article "The Use of Interspecies Scaling in Toxicokinetics", pages: 42 - 46
POLISHCHUK, P: "CReM: chemically reasonable mutations framework for structure generation", J. CHEMINFORM, vol. 12, 2020, pages 28, XP093187884, DOI: 10.1186/s13321-020-00431-w
S. M. BERGE ET AL., J PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
SAE WOONG PARK ET AL: "Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis", CHEMISTRY & BIOLOGY, vol. 22, no. 1, 1 January 2015 (2015-01-01), GB, pages 76 - 86, XP055534978, ISSN: 1074-5521, DOI: 10.1016/j.chembiol.2014.11.012 *
SAMBROOKRUSSELL: "Molecular Cloning", 2001, COLD SPRING HARBOR LABORATORY PRESS
T. HIGUCHIV. STELLA: "Immunochemical Methods In Cell And Molecular Biology", vol. III, 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS, pages: 137 - 149
WESTERFIELD, M: "The zebrafish book. A guide for the laboratory use of zebrafish", vol. 154-155, 2000, UNIV. OF OREGON PRESS
WONG, FZHENG, E.JVALERI, J.ADONGHIA, N.MANAHTAR, M.NOMORI, SLI, ACUBILLOS-RUIZ, AKRISHNAN, AJIN, W ET AL.: "Discovery of a structural class of 1067 antibiotics with explainable deep learning", NATURE, 2023

Similar Documents

Publication Publication Date Title
US12469580B2 (en) In silico discovery of effective antimicrobials
US12325678B2 (en) Anti-fungals compounds targeting the synthesis of fungal sphingolipids
Thamban Chandrika et al. Alkylated piperazines and piperazine-azole hybrids as antifungal agents
US10940163B2 (en) Bicarbonate as a potentiator for antimicrobial agents
CN101070304B (en) Quinoline derivatives and their use as mycrobacterial inhibitors
Pandit et al. Current updates on oxazolidinone and its significance
JP4515027B2 (en) Substituted heterocyclic compounds for treating multidrug resistance
O’Brien et al. Potent irreversible inhibitors of LasR quorum sensing in Pseudomonas aeruginosa
US6596723B1 (en) Fungal efflux pump inhibitors
Sugar et al. Effectiveness of quinolone antibiotics in modulating the effects of antifungal drugs
MX2014013910A (en) High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions.
US10350217B2 (en) Antifungal agents and uses thereof
Seferyan et al. Multicationic Quaternary Ammonium Compounds: A Framework for Combating Bacterial Resistance
NO20071314L (en) Peptidic vasopressin receptor agonists
US20150353545A1 (en) Quorum sensing inhibitors
JP2015505325A (en) Compounds and methods for treating candidiasis and Aspergillus infections
Coandă et al. Small schiff base molecules—a possible strategy to combat biofilm-related infections
do Couto et al. Antifungal activity of the piroctone olamine in experimental intra-abdominal candidiasis
KR20170052613A (en) Use of cysteamine in treating infections caused by yeasts/moulds
Wang et al. Novel Nitric Oxide Donor–Azole Conjugation Strategy for Efficient Treatment of Cryptococcus neoformans Infections
CN101522195B (en) Pharmaceutical composition containing phenylamidine derivatives and methods of using the pharmaceutical composition in combination with antifungal agents
CN101151032B (en) Pharmaceutical composition and method using antifungal agent in combination
WO2025212960A1 (en) Antimicrobials and discovery thereof
Zhang et al. Hybrid Molecules of Benzothiazole and Hydroxamic Acid as Dual-Acting Biofilm Inhibitors with Antibacterial Synergistic Effect against Pseudomonas aeruginosa Infections
CN116836083A (en) Functional derivative compounds of alanine and proline amino acids and pharmaceutical compositions containing the same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25719946

Country of ref document: EP

Kind code of ref document: A1