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WO2017027968A1 - Adjuvants à base d'antibiotiques hybrides surmontant la résistance dans pseudomonas aeruginosa - Google Patents

Adjuvants à base d'antibiotiques hybrides surmontant la résistance dans pseudomonas aeruginosa Download PDF

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WO2017027968A1
WO2017027968A1 PCT/CA2016/050959 CA2016050959W WO2017027968A1 WO 2017027968 A1 WO2017027968 A1 WO 2017027968A1 CA 2016050959 W CA2016050959 W CA 2016050959W WO 2017027968 A1 WO2017027968 A1 WO 2017027968A1
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tobramycin
tether
aminoglycoside
compound
pump inhibitor
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Inventor
Frank Schweizer
Bala Kishan GORITYALA
Goutam GUCHHAIT
Xuan YANG
George G. Zhanel
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University of Manitoba
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University of Manitoba
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/18—Testing for antimicrobial activity of a material
    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
    • G01N2333/21—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Pseudomonadaceae (F)

Definitions

  • Pseudomonas aeruginosa is the leading cause of nosocomial infections and chronic lung infections in cystic fibrosis patients with mortality rates ranging from 30-50%' 2 .
  • infections caused by P. aeruginosa are particularly difficult to treat as the organism is both intrinsically resistant and capable of acquiring resistance to most antibiotics 3 .
  • This is in large part the result of the low permeability of its outer membrane which is 12-100 times lower than that of E. coli and is caused by selective porins 4 .
  • the reduced uptake of antibiotic across the outer membrane in P. aeruginosa enables secondary adaptive resistance mechanisms to work more efficiently including efflux due to the intrinsic or induced expression of efflux pumps and antibiotic- modifying enzymes 3 .
  • Clinically useful anti-pseudomonal antibiotics are limited to select penicillins (eg. piperacillin tazobactam), cephalosporins (eg. ceftazidime), carbapenems (eg. imipenem), fluoroquinolones (eg. ciprofloxacin), aminoglycosides (eg. tobramycin) and colistin but resistance to these agents is steadily increasing with few novel anti-pseudomonal agents in clinical development 4 .
  • penicillins eg. piperacillin tazobactam
  • cephalosporins eg. ceftazidime
  • carbapenems eg. imipenem
  • fluoroquinolones eg. ciprofloxacin
  • aminoglycosides eg. tobramycin
  • colistin colistin
  • tobramycin and ciprofloxacin possess multiple modes of action and distinct uptake mechanisms.
  • Tobramycin's mode of action is concentration dependent. At low-concentrations ( ⁇ 4 ⁇ g/mL), tobramycin binds to the 30S ribosomal subunit, thereby leading to the disruption of protein synthesis while at higher concentrations (> 8 disruption of the outer membrane is observed 5 .
  • the antimicrobial action of the fluoroquinolones is mediated through the inhibition of two type II DNA topoisomerase enzymes, DNA gyrase and topoisomerase IV which play an essential role in DNA relaxation, partitioning replicated chromosomal DNA during cell division and decatenation reactions 6 .
  • tobramycin and ciprofloxacin also display different uptake mechanisms.
  • the uptake of aminoglycosides into Gram-negative bacteria involves interactions at sites at which divalent cations cross-bridge adjacent polyanionic lipopolysaccharide (LPS) that causes destabilization of the outer membrane and results in self-promoted uptake of the antibiotic or other extracellular molecules 7
  • LPS polyanionic lipopolysaccharide
  • uptake of fluoroquinolones in Gram-negative bacteria does not occur by self-promoted uptake, but rather involves diffusion across the cell membrane with uptake through the porin pathway 8 .
  • Multitargeting antibiotics are expected to limit the frequency of spontaneous resistance that can arise from mutation in the target gene 29 .
  • One approach to design multitargeting antibacterials involves the covalent attachment of two different pharmacophores that inhibit dissimilar targets in the bacterial cell generating hybrid antibiotics 14 .
  • EPIs Resistance-Nodulation-Division
  • perturbation or disruption of the proton motive force (PMF) which energize efflux pumps can also be used to block the function of RND pumps 36,37 .
  • PMF proton motive force
  • EPIs have been described 38 including 1 -(1 -naphthylmethyl)- piperazine (NMP) 39 , paroxetine (PAR) 38,40 and dibasic peptides like DBP 41 ( Figure 8) and for some, efficacy has been established in animal models of infection 42 .
  • NMP is a broad spectrum EPI which synergizes with multiple classes of antibiotics including tetracyclines, fluoroquinolones, macrolides, penicillins and rifampicin against certain clinically relevant Gram-negative pathogens like E.
  • PAR potentiates tetracyclines and fluoroquinolones in Gram-positive and Gram-negative bacteria excluding P. aeruginosa 40 .
  • EPIs such as DBP, NMP and PAR inhibit efflux of tetracycline and fluoroquinolone antibiotics in certain Gram-negative bacteria they are still subject to intrinsic resistance in organisms like P. aeruginosa.
  • a compound comprising an aminoglycoside connected to a fluoroquinolone or an efflux pump inhibitor.
  • a method of enhancing the anti-bacterial activity of an antibacterial compound comprising co-administering said antibacterial compound with a second compound comprising an aminoglycoside connected to a fluoroquinolone or efflux pump inhibitor.
  • a method of preparing a medicament for treatment of a bacterial infection comprising admixing a compound comprising an aminoglycoside connected to a fluoroquinolone or efflux pump inhibitor and a suitable excipient.
  • a method of determining if an agent of interest has antibacterial activity comprising:
  • a method of determining the effect of a compound comprising an aminoglycoside connected to a fluoroquinolone or an efflux pump inhibitor on the antibacterial activity of an agent of interest comprising:
  • a method of determining if an agent of interest has antibacterial activity comprising:
  • a method of potentiating a tetracycline antibiotic or mitomycin C comprising coadministering the tetracycline antibiotic or mitomycin C with a compound comprising tobramycin connected to a ciprofloxacin or moxifloxacin or an efflux pump inhibitor.
  • a compound comprising tobramycin connected to a ciprofloxacin or moxifloxacin or an efflux pump inhibitor, for potentiating a tetracycline antibiotic or mitomycin C.
  • FIG. 1 Structure of tobramycin-ciprofloxacin hybrids.
  • Compounds la-le are hybrids with a tether attached to the C-5 position of tobramycin while compounds 2 and 3 contain the tether at the C-2" or C-6" ⁇ respectively.
  • Compounds 4 and 5 are fragments of lead structure le.
  • FIC index were governed by the aliphatic chain leanth that connects tobramycin and ciprofloxacin among hybrids. High FIC indices of 4 and 5 showcase the importance of dual antibiotic role in the hybrid molecule (b) Potentiation of ciprofloxacin or moxifloxacin by le in MDR and XDR clinical isolates of P. aeruginosa strains as shown by the FIC index, (c) Enhanced Efficacy of combination of le with moxifloxacin in in vivo was demonstrated in Galleria mellonella infection model in a dose- dependent fashion.
  • the % luminiscence was calculated compared to no antibiotic control (assumed to be 100%). Each data point represents an average luciferase activity of the triplicates with +/- percentage error.
  • the IC50 values ( ⁇ ) tobramycin (0.0062 ⁇ 0.0002), le (8.05 ⁇ 0.57), 2 (0.97 ⁇ 0.05) and 3 (3.44 ⁇ 0.09) were obtained as described in biological methods, (c) Inhibition of P. aeruginosa DNA gyrase A activity in the presence of ciprofloxacin, le, 2 and 3.
  • FIG. 1 Overview of tobramycin-moxifloxacin hybrids used in this study. Hybrids differ in the linkage to tobramycin. In hybrid 10 moxifloxacin is linked via a C12-tether to the C-5 position of tobramycin while hybrids 20 and 30 are linked to the C-2" and C-6"-positions in tobramycin.
  • FIG. 5 Effects of hybrid 10 on bacterial killing and in vivo efficacy.
  • A Time-kill curves showing the effect of varying concentrations of hybrid 10 and MIC concentration of colistin (Col) on the viability of P. aeruginosa PAOl cells grown in MH broth. No colony-forming units (CFU) were found with 10 at 2 x MIC (blue) after 24 hours. Experiment was performed three times independently and each data point is an average of three determinations ⁇ SEM.
  • B Enhanced dose dependent efficacy of hybrid 10 in comparison with tobramycin (TOB) and moxifloxacin (MOX) in XDR P.
  • aeruginosa (#104354) over a period of 24 h was demonstrated in Galleria mellonella in vivo infection model.
  • Larvae infected with #104354 (106 CFU/mL) resulted in 73% killing after 24 h.
  • single dosage monotherapy 50 mg kg of moxifloxacin, or tobramycin or hybrid 10 resulted in 27%, 20% or 100% survival of the larvae, respectively, after 24 h. No killing was observed due to physical trauma when larvae were injected with equal volumes of PBS.
  • FIG. 6 Effects of hybrid 10 on the outer membrane. Concentration-dependent permeabilization of the outer membrane by tobramycin-moxifloxacin hybrid 10 is indicated by the accumulation of 1 -N-phenylnaphthylamine (NPN) in P. aeruginosa PAOl cells. 50 ⁇ g mL (medium plum), 32 ⁇ g mL (cyan), 16 ⁇ g mL (gold), or 8 ⁇ g/mL (pale lavender) of hybrid 10 were used, along with 5 ⁇ g/mL colistin (Col) (pale violet red) as positive control. Hybrid 10 was added at 120 seconds. Experiment was performed in triplicate and each data point is an average of three determinations ⁇ SEM. (B) Synergistic FIC index of hybrid 10 in combination with various classes of antibiotics against PAOl.
  • NPN -N-phenylnaphthylamine
  • FIG. 7 Protein translation activity, gyrase A activity and emergence of resistance.
  • A Inhibition of in vitro protein translation in E. coli S30 extract by tobramycin, moxifloxacin, hybrid 10 and 20. Protein translation assays were performed as described in methods section. The percentage luminescence was calculated compared to no antibiotic control (assumed to be 100%). Each data point represents an average luciferase activity of the triplicates with ⁇ percentage error. The IC50 values ( ⁇ ) for tobramycin (0.0062 ⁇ 0.0002), 10 (4.7 ⁇ 0.21), and 20 (0.13 ⁇ 0.003) were obtained.
  • B Inhibition of P.
  • FIG. 1 Structures of the efflux pump inhibitors (EPIs) NMP, PAR and DBP and tobramycin (TOBHinked EPI conjugates TOB -NMP (lOOa-f), TOB-PAR (200) and TOB-DBP (300).
  • EPIs efflux pump inhibitors
  • Figure 9 (a) Enhanced dose-dependent efficacy of a combination of conjugate lOOf and minocycline in XDR P. aeruginosa #101856 over a period of 24 h was demonstrated in a Galleria mellonella in vivo infection model. Combination therapy (37.5 mg/kg of lOOf + 37.5 mg/kg of minocycline) or (75 mg/kg of lOOf + 75 mg kg of minocycline) resulted in 10% or 77% survival of the larvae, respectively after 24 h.
  • FIG. 1 In- vivo studies: Synergy demonstration between mitomycin C (MYT-C) and adjuvant 10 in Galleria mellonella infection model infected with XDR P. aeruginosa strain # 262. Mitomycin C (10 mg/kg) provided low level of protection ( ⁇ 20%) while combination therapy of adjuvant 10 (10 mg kg) and Mitomycin C (10 mg/kg) produced 80% survival after 24 hours.
  • TOB tobramycin
  • a compound comprising an aminoglycoside connected to a fluoroquinolone or efflux pump inhibitor.
  • any suitable tether or linker known in the art may be used to connect the fluoroquinolone and the aminoglycoside provided that the tether is sufficiently flexible and sufficiently long that the aminoglycoside and the fluoroquinolone are able to function as discussed below. However, if the tether gets too long, some of the activity of the compound may be lost.
  • the tether or linker may be approximately 2-24 carbons long. As will be appreciated by one of skill in the art, this does not mean that the tether or linker necessarily needs to include 2-24 carbon molecules, merely that the tether or linker must be of the same approximate length as 2-24 carbon molecules.
  • the tether may comprise a length of 2-24, 3-24, 4-24, 5-24, 6-24, 2-23, 2-22, 2-21, 2-20, 2-19, 2-18, 3-23, 3-22, 3-21, 3-20, 3-19, 3-18, 4-23, 4-22, 4-21, 4- 20, 4-19, 4-18, 5-23, 5-22, 5-21, 5-20, 5-19, 5-18, 6-23, 6-22, 6-21, 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12 carbon atoms.
  • the aminoglycoside is tobramycin.
  • the fluoroquinolone is ciprofloxacin or moxifloxacin.
  • the compound is tobramycin connected to ciprofloxacin or moxifloxacin or an efflux pump inhibitor.
  • the efflux pump inhibitor is selected from the group consisting of NMP, PAR and DBP.
  • the tobramycin is tethered to the ciprofloxacin or moxifloxacin or efflux pump inhibitor.
  • the tether is a flexible tether, as shown in Figure 1.
  • the tether may comprise 4-12 repeating alkyl units.
  • the tether may be connected to any suitable position on tobramycin, for example, a hydroxyl group.
  • the hydroxyl group may be for example, at the C-5 position, the C-4' position, the C-4" position, the C-2" position or the C- 6" position on tobramycin.
  • the preferred attachment site for ciprofloxacin is the secondary amino group of the piperazine ring in ciprofloxacin as other attachment at other positions may interfere with the mode of action of ciprofloxacin.
  • a method of treating a bacterial infection in an individual in need of such treatment comprising administering to said individual an effective amount of a compound comprising an aminoglycoside connected to a fluoroquinolone or efflux pump inhibitor.
  • the aminoglycoside is connected to the fluoroquinolone via a tether, as discussed above.
  • the aminoglycoside is tobramycin.
  • the fluoroquinolone is ciprofloxacin or moxifloxacin.
  • the efflux pump inhibitor is selected from the group consisting of NMP, PAR and DBP.
  • the compound is tobramycin connected to ciprofloxacin or moxifloxacin or the efflux pump inhibitor, as discussed above.
  • the tobramycin is tethered to the ciprofloxacin, moxifloxacin or efflux pump inhibitor.
  • any suitable tether or linker known in the art may be used to connect the tobramycin and the ciprofloxacin, moxifloxacin or efflux pump inhibitor provided that the tether is sufficiently flexible and sufficiently long that the tobramycin and the ciprofloxacin, moxifloxacin or efflux pump inhibitor are able to function as discussed below.
  • the agent of interest is attached to the aminoglycoside by a tether.
  • the tether may be a flexible tether.
  • the tether may be selected from the group consisting of but by no means limited to a flexible alkyl linker, an unsaturated alkyl linker, an ethylene glycol linker or an aromatic linker.
  • the tether may comprise a length of 2-24, 3-24, 4-24, 5-24, 6-24, 2-23, 2-22, 2-21, 2-20, 2-19, 2-18, 3-23, 3-22, 3-21, 3-20, 3-19, 3-18, 4-23, 4-22, 4-21, 4-20, 4-19, 4-18, 5- 23, 5-22, 5-21, 5-20, 5-19, 5-18, 6-23, 6-22, 6-21, 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12 carbon atoms.
  • the aminoglycoside is tobramycin.
  • the tether is a flexible tether, as shown in Figure 1.
  • the tether may comprise 4-12 repeating alkyl units.
  • the tether may be connected to any suitable position on tobramycin, for example, a hydroxyl group.
  • the hydroxyl group may be for example, at the C-5 position, the C-4' position, the C-4" position, the C-2" position or the C-6" position of the tobramycin.
  • the bacterial infection is caused by a pathogenic gram-negative bacteria.
  • the pathogenic gram-negative bacteria may be for example but by no means limited to E. coli, Acetinobacter, Salmonella, Shigella, Enterobacteriaceae, Pseudomonas, Moraxella, Heliobacter, Stenotrophomonas, Bdellovibrio, Legionella and the like.
  • the pathogenic gram- negative bacteria is P. aeruginosa, E. coli or Acetinobacter baumannii.
  • the P. aeruginosa strain is an extremely drug-resistant strain of P. aeruginosa.
  • an "effective amount” is an amount that is sufficient to accomplish at least one of the following: reduction in the severity of the symptoms associated with the bacterial infection; and reduction in the CFU per ml of bacteria in a sample taken from the individual. As discussed herein, this may be accomplished by increasing or enhancing the anti-bacterial activity of another compound. For example, while not wishing to be bound to a particular theory or hypothesis, the inventors believe that the compounds described herein enhance the permeability of the gram-negative outer membrane and thereby in effect act as a delivery system. As such, in these embodiments, an “effective amount” is an amount that is sufficient to enhance the permeability of the outer membrane of the infective bacteria so that an antibacterial agent can enter the bacterial cell. As will be appreciated by one of skill in the art, this means that a wide variety of compounds that have bacteria targets but cannot cross the outer membrane on their own can now be considered to be anti-bacterial agents when used in combination with the compounds of the invention.
  • the compound may be co-administered with a second antibiotic.
  • antibiotics and antibacterial agents including but by no means limited to fluoroquinolones, beta- lactams (penicillins, cephalosporins (ceftazidimes and the like), carbapenems, monobactams), rifampicin, vancomycin, trimethoprim, trimethoprim plus sulfamethoxazole, colistin, polymyxin, chloramphenicol, novobiocin, and macrolides (erythromycin and the like).
  • antibiotics and antibacterial agents including but by no means limited to fluoroquinolones, beta- lactams (penicillins, cephalosporins (ceftazidimes and the like), carbapenems, monobactams), rifampicin, vancomycin, trimethoprim, trimethoprim plus sulfamethoxazole, colistin, polymyxin, chloramphenicol, novobiocin, and macro
  • antibiotic agents such as fluoroquinolones (ciprofloxacin, moxifloxacin, levofloxacin and the like), clindamycin, streptogramins, sulfonamides and monobactams.
  • a method of enhancing the antibacterial activity of an antibacterial compound comprising co-administering said antibacterial compound with a second compound comprising an aminoglycoside connected to a fluoroquinolone or efflux pump inhibitor as discussed above.
  • the aminoglycoside is connected to the fluoroquinolone via a tether as discussed above.
  • the aminoglycoside is tobramycin.
  • the fluoroquinolone is ciprofloxacin or moxifloxacin.
  • the efflux pump inhibitor is selected from the group consisting of MP, PAR and DBP.
  • the compound is tobramycin connected to ciprofloxacin, moxifloxacin or an efflux pump inhibitor.
  • the tobramycin is tethered to the ciprofloxacin as discussed above.
  • any suitable tether or linker known in the art may be used to connect the tobramycin and the ciprofloxacin, moxifloxacin and efflux pump inhibitor provided that the tether is sufficiently flexible and sufficiently long that the tobramycin and the ciprofloxacin, moxifloxacin or efflux pump inhibitor are able to function as discussed herein.
  • an effective amount of the second compound is co-administered with the antibiotic compound.
  • an "effective amount” is an amount that is sufficient to at least increase the effectiveness of the anti-bacterial compound, for example, such that less of the first compound is required or the time between administrations is increased or the severity of the bacterial infection is reduced to a greater extent than on administration of the anti-bacterial compound alone.
  • Other methods for detenrdning an effective amount of the compound to be administered to the individual will be apparent to one of skill in the art and may depend on many other factors, for example, the age and general condition of the individual and the severity of the infection and/or symptoms associated with the infection.
  • a compound comprising tobramycin connected to a ciprofloxacin or moxifloxacin or an efflux pump inhibitor to potentiate tetracycline antibiotics or mitomycin C.
  • the efflux pump inhibitor is selected from the group consisting of NMP,
  • tetracycline antibiotics are well known to those of skill in the art and as such suitable tetracycline antibiotics that can be used in this aspect of the invention will be well known to those of skill in the art.
  • the tetracycline antibiotic may be for example but by no means limited to minocycline, tigecycline, doxycycline and the like.
  • any suitable tether or linker known in the art may be used to connect tobramycin to the ciprofloxacin, moxifloxacin or efflux pump inhibitor provided that the tether is sufficiently flexible and sufficiently long that tobramycin and the ciprofloxacin or moxifloxacin or an efflux pump inhibitor are able to function as discussed below. However, if the tether gets too long, some of the activity of the compound may be lost.
  • the tether or linker may be approximately 2-24 carbons long. As will be appreciated by one of skill in the art, this does not mean that the tether or linker necessarily needs to include 2-24 carbon molecules, merely that the tether or linker must be of the same approximate length as 2-24 carbon molecules.
  • the tether is a flexible tether.
  • the tether may be selected from the group consisting of but by no means limited to a flexible alkyl linker, an unsaturated alkyl linker, an ethylene glycol linker or an aromatic linker.
  • the tether may comprise a length of 2-24, 3-24, 4-24, 5-24, 6-24, 2-23, 2-22, 2-21, 2-20, 2-19, 2-18, 3-23, 3-22, 3-21, 3-20, 3-19, 3-18, 4-23, 4-22, 4-21, 4- 20, 4-19, 4-18, 5-23, 5-22, 5-21, 5-20, 5-19, 5-18, 6-23, 6-22, 6-21, 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12 carbon atoms.
  • the tether may comprise 4-12 repeating alkyl units.
  • the tether may be connected to any suitable position on tobramycin, for example, a hydroxyl group.
  • the hydroxyl group may be for example, at the C-5 position, the C-4' position, the C-4" position, the C-2' ' position or the C-6" position on tobramycin.
  • a compound comprising an aminoglycoside connected to a fluoroquinolone as discussed above for enhancing the antibacterial activity of an agent.
  • the agent does not necessarily have antibacterial properties on its own and may need to be co-administered with the compound in order to enter the bacterial cell.
  • the agent may have antibacterial properties on its own but these antibacterial properties may be enhanced by increased entry of the agent into the bacterial cell by the membrane permeability enhancing activity of the agent.
  • a method of preparing a medicament for treatment of a bacterial infection comprising admixing a compound comprising an aminoglycoside connected to a fluoroquinolone or an efflux pump inhibitor and a suitable excipient.
  • the compound may be formulated for co-administration with an agent having anti-bacterial properties either alone or when administered in combination with the compound, as discussed herein.
  • the aminoglycoside is tobramycin.
  • the fluoroquinolone is ciprofloxacin or moxifloxacin, as discussed herein.
  • the efflux pump inhibitor is selected from the group consisting of NMP, PAR andDBP.
  • the compounds described herein serve as adjuvants and can potentiate other classes of antibiotics and antibacterial agents.
  • this includes antibacterial agents which may not have antibacterial activity on their own due to an inability to cross the outer membrane of the bacterial target.
  • many known and unknown compounds can interact with validated antibacterial targets such as for example but by no means limited to enzymes, RNA, DNA, proteins, and the like, but possess no or poor antibacterial activity because they cannot cross the bacterial membranes in gram-negative organisms.
  • one function of the tobramycin- ciprofloxacin hybrids is to enhance the permeability of the outer membrane in P. aeruginosa. This facilitates cell penetration and may convert non antibacterial agents into antibacterial ones. As such the adjuvants would serve as a delivery system.
  • a method of determining if an agent of interest has antibacterial activity comprising: co-adniinistering the agent of interest with a com ound comprising an aminoglycoside connected to a fluoroquinolone or efflux pump inhibitor to a bacterium of interest; and
  • the agent of interest may be any compound thought, proposed or hypothesized to have an antibacterial effect once inside the cell of a gram-negative bacterium.
  • any suitable gram-negative bacterium may be used for the screening process.
  • the compound and the agent of interest may be administered to a population or culture of gram-negative bacterial cells and survival may be determined by comparing survival of bacteria treated with the agent of interest and the compound to survival of bacteria treated only with the agent of interest.
  • a method of determining the effect of a compound comprising an aminoglycoside connected to a fluoroquinolone or efflux pump inhibitor on the antibacterial activity of an agent of interest comprising:
  • the effect of the compounds of the invention on any agent, whether it has antibacterial properties, that is, bactericidal (killing of bacteria) or bacteriostatic (inhibition of growth) on its own or not, can be determined.
  • Hybrid le was selected for further combination studies against a panel of 8 clinical P. aeruginosa isolates including six MD (non-susceptible or resistant to > 3 chemically unrelated anti- pseudomonal classes), and six extremely-drug resistant (XDR) (non-susceptible or resistant to > 5 chemically unrelated anti-pseudomonal classes).
  • the panel also included two colistin-non-susceptible or resistant P. aeruginosa strains.
  • the fluoroquinolone-resistant isolates contained a single mutation (T83-I) in GyrA which was absent in the colistin-non-susceptible or resistant strains.
  • aeruginosa strains we observed additive effects or weaker synergistic effects (FIC index ⁇ 0.31 - 0.75) but still observed 16-fold fold potentiation of moxifloxacin and 2- to 8-fold potentiation of ciprofloxacin at 1 ⁇ 4 MIC of hybrid le.
  • the reduced synergistic effects or additive effects of le against colistin-resistant P. aeruginosa likely reflects a reduced self-promoted uptake caused by transfer of cationic 4-amino-4-deoxy-l-arabinose to lipid A in these organisms 14 .
  • Combination studies of moxifloxacin with various membrane-active agents confirmed that the observed synergistic effects of le were not the result of nonspecific membranolytic effect. This is in accordance with the observed low hemolytic activity of le which resulted in ⁇ 10% hemolytic activity at 1000 ⁇ g mL and low cytotoxic properties against cancer cell lines.
  • hybrid antibiotics consisting of tobramycin and ciprofloxacin are powerful multimodal adjuvants that can restore antibacterial activity and enhance efficacy with fluoroquinolones in MDR and XDR P. aeruginosa.
  • the strong synergistic effects of le against P. aeruginosa are also observed with other classes of antibiotics except carbapenems and aminoglycosides.
  • aeruginosa PA01 (b) is less prone to efflux than 2 nd and 3 rd generation fluoroquinolone antibiotics and (c) interacts as a hydrophobic fluoroquinolone more strongly with the cytoplasmic membrane than ciprofloxacin.
  • the secondary amino function in moxifloxacin was selected for point of modification as alkylation of this function retains potent antibacterial activity against bacterial pathogens 32 .
  • a C-12 tether length was selected based on previous results obtained with the tobramycin-ciprofloxacin hybrid antibiotics that demonstrated that this tether length is optimal for outer membrane penetration and synergism with other classes of antibiotics in P. aeruginosa 11 , We also prepared hybrids 20 and 30 bearing a tether at the C-2"- and C-6 "-positions to study how the nature of the tobramycin linkage affects the antibacterial activity.
  • hybrids 10, 20 and 30 were tested for antibacterial activity by determining the minimal inhibitory concentration (MIC) against select Gram-negative and Gram-positive bacteria (Table 1).
  • MIC minimal inhibitory concentration
  • MRSA methicillin-resistant Staphylococcus aureus
  • the promising antipseudomonal properties of hybrid 10 provided the rationale to study the antibacterial activity of 10 against a select panel of MDR and XDR P.
  • aeruginosa isolates obtained from multiple Canadian hospitals which are resistant to tetracyclines (doxycycline), cephalosporins (cefepime), carbapenems (meropenem and imipenem), fluoroquinolones (ciprofloxacin and moxifloxacin) and aminoglycosides (tobramycin and gentamicin) but remain susceptible to colistin.
  • aeruginosa PAOl at 2x MIC concentration over a 24 hour time period (Fig. 5A).
  • hybrid 10 causes ⁇ 2.5% hemolysis of human erythrocytes at 1000 ⁇ g/mL and shows low cytotoxicity CC 50 » 30 ⁇ M against cancer cell lines.
  • aeruginosa strain #104354 resistant to all' classes of antipseudomonal agents except colistin
  • injection of 10 or tobramycin or moxifloxacin at 2h post infection a single dose of moxifloxacin (50 mg/kg) or tobramycin (50 mg/kg) or no drug resulted in 27% or 20% or 27% survival of the larvae at 24 h, respectively mdicating that both antibiotics provide insufficient protection.
  • single dose therapy (50 mg kg) of hybrid 10 resulted in 100% survival after 24 h (Fig. 5B).
  • hybrid 10 strongly synergizes with the fluoroquinolones ciprofloxacin and moxifloxacin against a panel of MDR and XDR P. aeruginosa isolates.
  • ciprofloxacin- susceptible MIC - 1 ⁇ g mL "1
  • CLSI breakpoints were reached for 6/6 ciprofloxacin-resistant, MDR, XDR or PDR P. aeruginosa isolates at 1 ⁇ 4 MIC of hybrid 10 ( ⁇ 2 ⁇ g/mL "1 ).
  • hybrids 10 and 20 showed a > 750-fold and >20-fold reduction in activity when compared to tobramycin (Fig. 7A).
  • hybrid 10 was a 20-fold less potent inhibitor of gyrase A when compared to moxifloxacin while hybrids 20 and 30 displayed equipotency than moxifloxacin (Fig. 7B).
  • aeruginosa PAOl was exposed to subinhibitory (MIC/2) concentrations of moxifloxacin, tobramycin and hybrid 10 during 24 successive subcultures (Fig. 7C).
  • MIC/2 subinhibitory concentrations of moxifloxacin, tobramycin and hybrid 10 during 24 successive subcultures
  • hybrids 20 and 30 displayed weak antibacterial activity.
  • the potent antipseudomonal properties of 10 cannot be rationalized by inhibition of protein translation or topoisomerase IV activity as this hybrid displays the weakest enzyme inhibitory activity against these enzymes among the three hybrids studied, but rather reflect other modes of action. Instead, hybrid 10 exerts its antipseudomonal effects by affecting the outer membrane integrity as supported by the TEM-study, NPN-permeability assay, PI staining and high synergy with outer membrane impermeable antibiotics.
  • hybrid 10 exerts pleiotropic effects by affecting the integrity of both outer- and inner membranes in P. aeruginosa.
  • the effects on the outer membrane result in enhanced cell penetration while the effects on the cytoplasmic membrane result in membrane depolarization that perturb the PMF.
  • the PMF plays a necessary role in excretion of proteins, toxic metabolites and efflux of antibiotics multimodal antibacterial effects of hybrid 10 are expected.
  • hybrid 10 possesses a low likelihood of resistance development when compared to its individual antibiotic components tobramycin and moxifloxacin.
  • the antibacterial activity using the minimal inhibitory concentration (MIC) of TOB-NMP conjugates lOOa-f were evaluated against a panel of clinically relevant pathogens but none of the conjugates demonstrated potent Gram-positive (MIC > 8 ⁇ /mL) or Gram-negative (MIC > 32 activity.
  • MIC minimal inhibitory concentration
  • FIC fractional inhibitory concentration
  • aeruginosa isolates in the presence of conjugates lOOf, 200 and 300 at a fixed concentration ( ⁇ 8 ⁇ g/mL, ⁇ 0.25 x MIC). These results show that all three conjugates lower the MIC of minocycline from 8-256 fold against the 8 selected MDR or XDR P. aeruginosa isolates. Importantly, in 96% of cases, conjugates 100f, 200 and 300 at a concentration of ⁇ 8 ⁇ g/mL ⁇ ⁇ 0.25 X MIC reached minocycline susceptibility (MIC ⁇ 1 ⁇ g/mL) against the 8-selected MDR or XDR P. aeruginosa isolates (Table 5).
  • conjugate 300 causes ⁇ 5% hemolysis of ovine erythrocytes at 1000 ⁇ g/mL and show low cytotoxicity (CC50 > 30 ⁇ ) against cancer cell lines while increased toxicity was noted for conjugate 300.
  • Tolerability studies in G. mellonella using a dosage of 200 mg/kg of lOOf or 200 showed no toxic effects up to 96 hours while a dose of 100 mg/kg of 300 resulted in 100% killing of the larvae after 24 hours.
  • the toxicity of conjugate 300 in the larvae prevented further use of this compound in the insect model.
  • Efficacy studies were performed by infecting the larvae with a lethal dose of (1.0 x 10 5 CFUs) of XDR P.
  • aeruginosa strain #101856 followed by injection of the drug combination 2 h post infection.
  • Monotherapy with a single dose (75 mg/kg) of minocycline or lOOf (75 mg/kg) or NMP (75 mg/kg) resulted in 100% killing of the larvae within 24 hours indicating that monotherapy was not able to provide protection of the larvae.
  • combination therapy (37.5 mg/kg lOOf + 37.5 mg/kg minocycline or 75 mg/kg lOOf + 75 mg/kg minocycline) resulted in 10% or 77% survival of the larvae, respectively, after 24 hours (Figure 9a).
  • efficacy was seen for conjugate 200.
  • single dose combination therapy 75 mg 200 + 75 mg minocycline
  • single dose monotherapy with minocycline 75 mg/kg
  • conjugate 200 75 mg/kg
  • conjugates lOOf permeabilizes the outer membrane of PAOl in a dose-dependent manner using the NPN (1-N-phenylnapthylamine) assay ( Figure 9b) 18 . Similar dose-dependent permeability was seen for conjugates 200 and 300. Next, we assessed whether the combination of conjugates lOOf, 200 or 300 with outer membrane impermeable antibiotics are synergistic in P. aeruginosa PAOl .
  • Mitomycin C is an antitumor antibiotic which crosslinks DNA. As seen in Table 7 we observed strong synergy of hybrids le and 10 with Mitomycin C. Furthermore, we also could demonstrate this effect in vivo using the Galleria mellonella infection model (Figure 11).
  • E.coli CAN-ICU 61714 (GEN-R) 4 64 64 ⁇ 0.25 8
  • Table 3B Effect of fixed concentration of ciprofloxacin ( ⁇ 4 ⁇ g mL “1 ; ⁇ 1/4 MIC) or moxifloxacin ( ⁇ 4 ⁇ mL "1 ; ⁇ 1/4 MIC) on MIC of hybrid 10

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Abstract

Des adjuvants qui sauvent les antibiotiques vis-à-vis des organismes multirésistants aux médicaments (MDR) sont une stratégie de combinaison prometteuse pour surmonter la résistance bactérienne. Tandis que la combinaison d'un antibiotique inhibiteur de la β-lactame β-lactamase a permis de rétablir l'efficacité antibactérienne, l'utilisation d'adjuvants pour rétablir l'efficacité de la fluoroquinolone dans des agents pathogènes multirésistants aux médicaments a été délicate. Nous décrivons ici des adjuvants comprenant un aminoglycoside lié à une fluoroquinolone ou à un inhibiteur de pompes d'efflux, qui rétablissent l'activité antibactérienne in vitro et augmentent l'efficacité in vivo d'antibiotiques de la famille des fluoroquinolones et des tétracyclines contre le Pseudomonas aeruginosa multirésistant aux médicaments et extrêmement résistant aux médicaments (XDR). Fig. 1: Tobramycin%%%Tobramycine Tether%%%Attache Ciprofloxacin%%%Ciprofloxacine
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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2018162928A1 (fr) * 2017-03-10 2018-09-13 Helperby Therapeutics Limited Procédé de restauration de l'efficacité d'un agent antibactérien
WO2018187867A1 (fr) * 2017-04-13 2018-10-18 University Of Manitoba Conjugués amphiphiles de tobramycine liés à un mimétique peptoïde à base de lysine par l'intermédiaire d'une attache
WO2020102910A1 (fr) * 2018-11-23 2020-05-28 University Of Manitoba Potentialisation d'antibiotiques bêtalactame et combinaisons d'inhibiteurs bêtalactame/bâtalactamase contre plusieurs médicaments et extrêmement résistants aux médicaments de pseudomonas aeruginosa à l'aide de conjugués de cyclame-tobramycine non ribosomal
WO2020232534A1 (fr) * 2019-05-17 2020-11-26 University Of Manitoba Novobiocine adaptée d'adjuvant de tobramycine homodimère servant d'agent antibactérien efficace contre des bactéries à gram négatif

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Title
GORITYALA ET AL.: "Hybrid antibiotic overcomes resistance in p. aeruginosa by enhancing outer membrane penetration and reducing efflux", J. MED. CHEM., vol. 59, no. 18, 13 August 2016 (2016-08-13), pages 8441 - 8455, XP055365369 *
GRAPSAS ET AL.: "Conjoint molecules of cephalosporins and aminoglycosides", ARCH. PHARM. ( WEINHEIM, vol. 334, no. 8-9, September 2001 (2001-09-01), pages 295 - 301, XP055365371 *
POKROVSKAYA ET AL.: "Design, synthesis, and evaluation of novel fluoroquinolone-aminoglycoside hybrid antibiotics", J. MED. CHEM., vol. 52, no. 8, 20 March 2009 (2009-03-20), pages 2243 - 2254, XP002599060 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018162928A1 (fr) * 2017-03-10 2018-09-13 Helperby Therapeutics Limited Procédé de restauration de l'efficacité d'un agent antibactérien
WO2018187867A1 (fr) * 2017-04-13 2018-10-18 University Of Manitoba Conjugués amphiphiles de tobramycine liés à un mimétique peptoïde à base de lysine par l'intermédiaire d'une attache
WO2020102910A1 (fr) * 2018-11-23 2020-05-28 University Of Manitoba Potentialisation d'antibiotiques bêtalactame et combinaisons d'inhibiteurs bêtalactame/bâtalactamase contre plusieurs médicaments et extrêmement résistants aux médicaments de pseudomonas aeruginosa à l'aide de conjugués de cyclame-tobramycine non ribosomal
WO2020232534A1 (fr) * 2019-05-17 2020-11-26 University Of Manitoba Novobiocine adaptée d'adjuvant de tobramycine homodimère servant d'agent antibactérien efficace contre des bactéries à gram négatif
US20220249441A1 (en) * 2019-05-17 2022-08-11 University Of Manitoba Homodimeric Tobramycin Adjuvant Repurposes Novobiocin as an Effective Antibacterial Agent Against Gram-Negative Bacteria

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