WO2018035617A1

WO2018035617A1 - Antibiotic carrier conjugates for the treatment of kidney infections

Info

Publication number: WO2018035617A1
Application number: PCT/CA2017/051004
Authority: WO
Inventors: Roger Leger; Jerome ROSSERT
Original assignee: Thrasos Therapeutics Inc Canada
Current assignee: Thrasos Therapeutics Inc Canada
Priority date: 2016-08-26
Filing date: 2017-08-25
Publication date: 2018-03-01
Anticipated expiration: 2019-02-26

Abstract

Provided are compounds having the Formula I : A_T(R_M)_V-(L_R)_W-R³CysX¹X²X³X⁴X⁵X⁶ProX⁷ThrCysR²XR³(R⁴)_S(R⁵)₁, (1); pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Also provided is the use of these compounds for the treatment of bacterial infections.

Description

ANTIBIOTIC CARRIER CONJUGATES FOR TH E TREATMENT OF KI DNEY

IN FECTIONS

RELATED APPLICATIONS

[ 000 1 ] This application claims priority to U .S. Provisional Application No.

62/380,073, filed August 26, 201 6, the entire contents of which arc incorporated herein by reference.

BACKGROUND

[ 0002 ] Antibiotics arc typically the first line of treatment for kidney infections. However, many antibiotics and their metabolites are excreted via the kidney due to its glomerular filtration, tubular secretion, or in some cases both. In cases where renal impairment (such as e.g., acute kidney injury or myeloma cast nephropathy) exists, the clearance of the antibiotic becomes of great clinical importance because of the altered excretions from the kidney. Sec e.g., medical investigation 1999; 33 (2): 43-46. Altered clearance can also impede the pharmacokinetics- absorption, distribution (including protein binding), and metabolism of the administered antibiotic. Finding alternative and more effective treatments for kidney infections, particularly in patients having renal impairment, is therefore of great importance.

SUMMARY OF THE INVENTION

[ 0003 ] It has been found that peptides having the formula

and pharmaceutically acceptable salts thereof, exhibit superior renal clearance (after infusion of 1 0 mg/kg of SEQ ID No. 27 for 2 hours to 6 rats, the percentage of intact peptide recovered in the urine was 1 00% ± 22% (mean i SD) Sec FIG. 4).

[ 0004 ] Having recognized this advantage, provided herein are compounds that incorporate these peptides in peptide/antibiotic conjugates type manner to improve e.g., the clearance rate of antibiotics. Such compounds include those having the Formula I :

A₁-(R_M (L_R)_w-J¹CyE^¹X²X^J-^X^sXⁱftoX⁷ThtCysJ²J (J (J^s)_l ( I); or a pharmaceutical salt thereof, wherein j' , X¹, X²,

J⁴, J⁵, L_R, R_M, A i , s, t, w, and v are as described herein.

[ 0005 ] In one aspect, other advantages from utilizing the compound of Formula 1 include an increase in urine concentration of the antibiotic, lower systemic distribution of the antibiotic, or decreased renal tubular toxicity of the antibiotic.

10006] Also provided herein are pharmaceutical compositions comprising the compounds of Formula I as well as the use of the disclosed compounds and compositions for treating bacterial infections (e.g., for treating kidney infections caused by bacteria in subjects with renal impairment).

BRIEF DESCRIPTION OF THE DRAWINGS

[0007 ] FIG. 1 illustrates the plasma pharmacokinetics following intravenous bolus injection of a portion of the compound of Formula I in rat.

10008 ] FIG. 2 illustrates the plasma pharmacokinetics following 2 hour intravenous infusion of a portion of the compound of Formula I in rat.

10009 ] FIG. 3 compares the plasma pharmacokinetics of two portions of the compound of Formula I after intraperitoneal injection in rat, where a.) shows a plot of peptide vs time at various concentrations; b.) shows a plot of steady state concentration (Css) as a function of. dose; and c.) shows a plot of the Area Under the Cure (AUC) as a function of dose.

[ 0010] FIG. 4 illustrates the urine recovery of a portion of the compound of Formula I

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

/. General Description of Compounds

1 01 1 ] In one aspect, provided arc compounds of Formula I:

Ar-( vi)v-(L_RXv-j'CysX¹X^:X¹X X⁵X'^:'ProX⁷ThrCysJ²J (J⁴),(J⁵)_l; (I)

or a pharmaceutical salt thereof, wherein

J¹ is Aha or Arg;

X¹ to X⁷ arc each independently a natural or non-natural amino acid;

s, t, w, and v are each independently 0 or I ;

J^: and y arc each independently Lys or Arg; J⁴, if present is Lys or Arg;

J³, if present is Lys or Arg;

L_K, if present is -C<=0)-Y-X^a;

Y is an optionally substituted linear or branched C i - o alky I, wherein one of more of the methylene units in the alky] are optionally and independently replaced by 0, S, NH, S(=0), S(0)₂, C(O), 3-pyrrolidinyl-2,5-dion- l -yl, or NHC(O);

X^a is bonded to J¹ and is -C(=0)NH- or S;

RM, if present, is a group capable of degrading in such a manner such that A_T is displaced from the remaining portion of Formula I; and

A _r is an antibody.

2. Definitions

[ 0012 ] 'Amino acid" refers to an organic compound containing an amine (-NH₂) and a carboxylic acid (-COOH) functional group, usually along with a side-chain specific to each amino acid. Amino acids can be classified according to the core structural functional groups' locations as alpha- (a-), beta- (β-), gamma- (γ-) or delta- (5-) amino acids; other categories relate to polarity, pH level, and side-chain group type (aliphatic, acyclic, aromatic, containing hydroxyl or sulfur, etc.). In one embodiment, amino acid includes

[ 0013 ] "Natural amino acid" is used interchangeably with protcinogenic amino acid and refers to the 20 standard amino acids encoded by the universal genetic code along with sclenocystcinc and pyrrolysinc. The 20 standard amino acids encoded by the universal genetic code include glycine, alanine, valine, leucine, isoleucinc, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparaginc, glutaminc, aspartate, glutamate, lysine, arginine, and histidine. Unless otherwise specified, when a natural amino acid is defined without indicating the stereochemistry it will be understood that the defined amino acid is present as the L-cnantiomcr. Thus, when used as part of a formula, the letter A or Ala means L-alanine.

( 0014] The full name of a natural amino acid and its corresponding thrcc-lcttcr or onc- lcttcr code are used interchangeably. For example, glycine is interchangeable with three letter abbreviation Gly or the one letter abbreviation G; alanine is interchangeable with three letter abbreviation Ala or the one letter abbreviation A, valine is interchangeable with three letter abbreviation Val or the one letter abbreviation V, leucine is

interchangeable with three letter abbreviation Leu or the one letter abbreviation L, isoleucine is interchangeable with three letter abbreviation lie or the one letter abbreviation I, proline is interchangeable with three letter abbreviation Pro or the one letter abbreviation P, phenylalanine is interchangeable with three letter abbreviation Phe or the one letter abbreviation F, tyrosine is interchangeable with three letter abbreviation Tyr or the one letter abbreviation Y, tryptophan is interchangeable with three letter abbreviation Trp or the one letter abbreviation W, serine is interchangeable with three letter abbreviation Ser or the one letter abbreviation S, threonine is interchangeable with three letter abbreviation Thr or the one letter abbreviation T, cysteine is interchangeable with three letter abbreviation Cys or the one letter abbreviation C, methionine is interchangeable with three letter abbreviation Met or the one letter abbreviation M, asparaginc is interchangeable with three letter abbreviation Asn or the one letter abbreviation N, glutamine is interchangeable with three letter abbreviation Gin or the one letter abbreviation Q, aspartate is interchangeable with three letter abbreviation Asp or the one letter abbreviation D, glutamate is interchangeable with three letter abbreviation Glu or the one letter abbreviation E, lysine is interchangeable with three letter abbreviation Lys or the one letter abbreviation K, arginine is interchangeable with three letter abbreviation Arg or the one letter abbreviation R, histidinc is interchangeable with three letter abbreviation His or the one letter abbreviation H, selcnocystcinc is interchangeable with three letter abbreviation Sec or the one letter abbreviation U, and pyrrolysine is interchangeable with three letter abbreviation Pyl or the one letter abbreviation O. hi one embodiment, the term "natural amino acid" or proteinogenic amino acid refers only to the 20 standard amino acids encoded by the universal genetic code, i.e., G, A, V, L, 1, P, F, Y, W, S, T, C, M, N, Q, D, E, , R, and H.

| 0015 ] "Non-natural amino acid" refers to a noti- proteinogenic amino acid that is not found in proteins (e.g., carnitine, gamma-ammob tyrk acid, and D-forms of natural amino acids except glycine) or not produced directly and in isolation by standard cellular machinery (e.g., hydroxyprol ine and selenomethionine). Other examples include, but are not limited to, β-amino acids (β3 and β2), homo-amino acids, alanine derivatives, alicyclic amino acids, arginine derivatives, asparaginc derivatives, aspartic acid derivatives, cysteine derivatives, 2,4-diaminobutyric acid, glycine derivatives, isoleucine derivatives, leucine derivatives, lysine derivatives (such as 6-aminohexanoic acid abbreviated herein as Aha), methionine derivatives, norleucine (nL) and norlcucine derivatives, phenylalanine derivatives, phcnylglycine derivatives, proline and pyruvic acid derivatives, pyroglutaminc derivatives, serine derivatives, threonine derivatives, tryptophan derivatives, norvaline derivatives, 2,3-diaminopropionic acid, ornithine derivatives, valine derivatives, linear core amino acids, and N-methyl amino acids. In one embodiment, the term "non-natural amino acid" refers only to D-fomis of the 20 standard amino acids encoded by the universal genetic code. These forms include D-Ala, D-Val, D-Lcu, D-lIc, D-Pro, D-Phc, D-Tyr, D-Trp, D-Ser, D-Thr, D-Cys, D-Met, D-Asn, D-Gln, D-Asp, D-GIu, D-Lys, D- Arg, and D-His.

[ 001 6 ] A "D-amino acid" or D-form of an amino acid means that the indicated amino acid is present as the D-enantiomcr. Shorthand notation for the D-cnantiomcr of an amino acid can be represented by an asterisk {*). For example, I* or I*lc, wherein * represents a D-atnino acid, refers to the D-enantiomer of lie (isoleucine).

[ 0017 ] The term "alkyl" refers to a monovalent saturated, straight- or branched-chain hydrocarbon radical, having unless otherwise specified (such as C |-Ci_S alkyl, C | -CK, alkyl, C C [₂ alkyl, C Cio alkyl, C Cs alkyl, C C₆ alkyl, and the like), 1 -20 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pcntyl, tcrt-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, and the like. Optional substitucnts for an alkyl group include groups that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. In some instances, optional substitucnts arc selected from halo (CI, Br, I, Fl), -0{Ci-Cio)alkyl, OH, NH,, N H(C,-Cio)alkyl, and N | (Ci-C₁₀)alkyl b.

[ 001 8 ] The compounds described herein may be present in the form of

pharmaceutically acceptable salts. Pharmaceutically acceptable salts are art-recognized and include e.g., relatively non-toxic inorganic and organic acid addition salts, or inorganic or organic base addition salts that arc suitable for human consumption. Examples of such salts include, but are not limited to, sodium, potassium, calcium, magnesium, acetate, benzoate, bicarbonate, carbonate, citrate, dihydrochloi ide, gluconate, glutamate, hydrochloride, and tartrate.

[ 001 ] The term "pharmaceutically acceptable carrier" refers to a non- toxic carrier, ad juvant, or vehicle that does not adversely affect the pharmacological activity of the peptide with which it is formulated, and which is also safe for human use.

Pharmaceutical ly acceptable carriers that may be used include, but are not limited to, ion exchangers, alumina, aluminum stearatc, magnesium stcaratc, lecithin, scrum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, dicalcium phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicatc, polyvinyl pyrrolidonc, polyvinylpyrrolidonc-vinyl acetate, ccllulosc-bascd substances (e.g., microcrystallinc cellulose, hydroxypropyl

mcthylccllulosc, hydroxypropyl mcthylccllulosc acetate succinate, hydroxypropyl mcthylccllulosc Phthalatc), starch, lactose monohydratc, mannitol, trehalose sodium lauryl sulfate, and crosscarmcllose sodium, polyethylene glycol, sodium

carboxymethylccllulose, polyacrylatcs, polymcthacrylatc, waxes, polycthylcnc- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[ 0020] The terms "subject" and "patient" may be used interchangeably, and mean a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[ 0021 ] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i. e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[ 0022 ] An "effective amount" or "therapeutical ly effective amount" is a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, for example, an amount which results in the prevention of or a decrease in the symptoms associated with a condition that is being treated, e.g., the conditions described herein.

3. Description of Exemplary Carriers

[ 0023 ] In a first embodiment, provided herein are compounds of the Formula I:

Ar-(RM)HLR -J¹Cy^¹X²X^{3 ,}X^JXⁱPraX⁷ThrCysJ (J )₁₁(J³),; (I) or a pharmaceutically acceptable salt thereof, wherein the variables arc as described above.

[ 0024] In a second embodiment, X^fl in the compound of Formula I is not Glu, Thr, Asn, or Asp; and X⁷ is not Glu or Asp, wherein the remaining variables in Formula 1 are as described above.

10025 ] In a third embodiment, ¹ in the compound of Formula I is selected from Arg, Lys, His, Pro, Cys, Thr, Ser, Gin, Glu, Leu, He, Met, Ala, Val, Gly, n-Leu, Met, Asp, and lie, wherein the remaining variables in Formula I arc as described above for Formula I or the second embodiment. Alternatively, X¹ in the compound of Formula I is selected from Arg, Gin, Glu, Leu, n-Leu, Met, Asp, and He, wherein the remaining variables in Fonnula I are as described above for Formula I or the second embodiment. In another alternative, X¹ in the compound of Formula I is selected from Gin, Leu, and n-Lcu, wherein the remaining variables in Fonnula I arc as described above for Formula I or the second embodiment.

[ 0026] In a forth embodiment, X² in the compound of Formula I is selected from a natural amino acid, wherein the remaining variables in Fonnula I arc as described above for Fonnula I or the second or third embodiment. Alternatively, X² in the compound of Formula I is selected from Ser, Thr, Cys, Met, Asn, Lys, Gin, His, Arg, Glu, and Asp, wherein the remaining variables in Fonnula I arc as described above for Formula I or the second or third embodiment. In another alternative, X² in the compound of Formula I is selected from Ser, Gin, His, Arg, Glu, and Asp, wherein the remaining variables in Formula I arc as described above for Fonnula I or the second or third embodiment. In yet another alternative, X~ in the compound of Formula I is selected from Gin and His, wherein the remain ing variables in Formula I are as described above for Formula 1 or the second or third embodiment.

[ 0027 ] In a fifth embodiment, X³ in the compound of Formula I is selected from a natural amino acid, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, or forth embodiment. Alternatively, X^? in the compound of Formula I is selected from Tyr, Trp, Phc, Scr, Thr, Cys, Met, Asn, Ala, Lys, His, Glu, Arg, and Asp, wherein the remaining variables in Formula I arc as described above for Formula I or the second, third, or forth embodiment. In another alternative, Χ in the compound of Formula I is selected from Tyr, Scr, Ala, Glu, Arg, and Asp, wherein the remaining variables in Formula I arc as described above for Formula I or the second, third, or forth embodiment. In yet another alternative, X^:t is selected from Tyr, Scr, Arg, and Asp, wherein the remaining variables in Formula I arc as described above for Formula I or the second, third, or forth embodiment.

[0028 ] In a sixth embodiment, X^J in the compound of Formula I is selected from a natural amino acid, wherein the remaining variables in Formula I arc as described above for Fomiula I or the second, third, fourth, or fifth embodiment. Alternatively, X^J in the compound of Fomiula I is selected froni Gly, Ala, Val, Leu, lie, Pro, Phc, Tyr, Trp, Asp, Glu, Lys, Arg, and His, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, or fifth embodiment. In another alternative, X⁴ in the compound of Formula I is selected from Leu, Asp, Gly, Tyr, Glu, and Arg, wherein the remaining variables in Formula I arc as described above for Formula I or the second, third, fourth, or fifth embodiment. In yet another alternative X⁴ in the compound of Formula I is selected from Leu, Asp, Tyr, and Arg, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, or fifth embodiment.

1 029] In a seventh embodiment, X⁵ in the compound of Formula I is selected from a natural amino acid, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, fifth, or sixth embodiment. Alternatively, X^s in the compound of Formula I is selected from Ser, Thr, Cys, Met, Asn, G in, Asp, Glu, Lys, Arg, and His, wherein the remaining variables in Formula I arc as described above for Formula 1 or the second, third, fourth, fifth, or sixth embodiment. In another alternative, X³ in the compound of Formula I is selected from Tyr, Ser, Arg, Glu, and Asp, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, fifth, or sixth embodiment.

10030] In an eighth embodiment, X⁽' in the compound of Formula I is selected from Gly, Ala, Val, Leu, He, Pro, Phe, Tyr, Tip, Ser, Cys, Met, Gin, Lys, Arg, and His, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, fifth, sixth, or seventh embodiment. Alternatively, X^ft in the compound of Formula I is selected from He, Leu, Pro, Val, Ala, Gly, His, Lys, and Arg, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, fifth, sixth, or seventh embodiment. In another alternative, X^f) in the compound of Formula I is selected from He, Leu, and Arg, wherein the remaining variables in Formula I arc as described above for Fonnula I or the second, third, fourth, fifth, sixth, or seventh embodiment. In yet another alternative, X^Cl in the compound of Fonnula I is selected from l ie and Leu, wherein the remaining variables in Formula I arc as described above for Formula I or the second, third, fourth, fifth, sixth, or seventh embodiment.

[ 003 1 ] In a ninth embodiment, X⁷ in the compound of Formula I is selected from Gly, Ala, Val, Leu, He, Pro, Phe, Tyr, Trp, Ser, Thr, Cys, Met, Asn, Gin, Lys, Arg, and His, wherein the remaining variables in Formula I are as described above for Formula 1 or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment. Alternatively, X⁷ in the compound of Formula 1 is selected from Tyr, Phe, His, Lys, Arg, and Trp, wherein the remaining variables in Fonnula I arc as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment. In another alternative, X⁷ in the compound of Formula I is selected from Tyr, Arg, and Trp, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment. In yet another alternative, X⁷ in the compound of Formula I is Tyr, wherein the remaining variables in Formula I arc as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[ 0032 ] In a tenth embodiment, s and t are each 0 in the compound of Fonnula 1, wherein the remaining variables in Formula I arc as described above for Formula 1 or the second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment. [0033 ] In an eleventh embodiment, s and t are each 1 in the compound of Formula I, wherein the remain ing variables in Formula I are as described above for Formula 1 or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[ 0034] In a thirteenth embodiment, J¹ in the compound of Formula I is Aha, wherein the remaining variables in Formula I are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[ 0035 ] Specific examples of the disclosed peptides arc provided in Table 1 as well as in the EXEMPLIFICATION sections. Phamiaeeutically acceptable salts as well as the neutral forms of these peptides are included in the present disclosure.

Table 1

SEQ ID

Sequence

No.

33 AhaCQQSYSEPYTC K

34 AhaCQQSYSI EYTC K

35 AhaCQQSYSIPETCK

36 AhaCQQSYSIPYECK

37 AhaCRQSYSIPYTC K

38 AhaCQRSYSIPYTC K

39 AhaCQQRYSI PYTCKK

40 AhaCQQSRSIPYTC K

41 AhaCQQSYRIPYTC K

42 AhaCQQSYSRPYTCK

43 AhaCQQ SYSI RYTCKK

44 AhaCQQSYSI PRTC K

45 AhaCQQSYSIPYRCKK

46 AhaCQQSY*SIPYTCK*K*K*K*

50 AhaCQQYSYLPITCK*K*

51 AhaCQQY SYLPITCR* R*

52 AhaCQQSYLPITCK*K*

53 AhaCQQY SLPITCK*K*

54 AhaCQQYDLPITCK*K*

55 AhaCQQ S YSI YTCR* R *

3. Description of Exemplary Linkers (L )

10036] Selection of the linker group of the compounds of Formula I, represented by - C{=0)-Y-X^a, will depend on the chemistry of the antibiotic and whether its target is intracellular, membrane disruption, or cel l wall biosynthesis.

[ 0037] In certain instances, as in a twelfth embodiment, Y in the linker group of the compounds of Formula I is an optionally substituted linear or branched C i -Cm alkyl, wherein one of more of the methylene units in the alkyl arc optionally and independently replaced by O, NH, S, C(=0), 3-pyrrolidinyl-2,5-dion- l-yl, or NHC(=0), and wherein the remaining variables for Formula I arc as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. Alternatively, Y in the linker group of the compounds of Formula I is an optionally substituted linear or branched C Oo alkyl, wherein one of more of the methylene units in the alkyl are optionally and independently replaced by NH, C(=0), 3-pyrrolidinyl-2,5- dion- 1 -yl, or NHC(=0), and wherein the remaining variables for Formula I arc as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. In another alternative, Y in the linker group of the compounds of Formula I is an optionally substituted linear or branched G-Gn alkyl, wherein one of more of the methylene units in the alkyl arc optionally and replaced by 3- pyrrolidinyl-2,5-dion- l-yl or HC(=0), and wherein the remaining variables for Formula I are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. In yet another alternative, Y in the linker group of the compounds of Formula I is a linear or branched G- o alkyl, wherein one of the methylene units in the alkyl is replaced by 3-pyrrolidinyl-2,5-dion- l -yl or NHC(=0), and wherein the remaining variables for Formula I arc as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. In yet another alternative, Y in the linker group of the compounds of Formula I is a linear C C₆ alkyl, wherein one of the methylene units is optionally replaced by 3-pyrrolidinyl- 2,5-dion-l -yl or NHC(=0), and wherein the remaining variables for Formula I arc as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

4. Description of Exemplary Re/ease Mechanisms R w

| 0038 ] In certain instances, i.e., when v is 1, the compounds of Formula I comprise a release group R_M. This release group is defined as a defined as a group capable of degrading in such a manner such that A_r is displaced from the remaining portion of Formula I. The selection (and presence) of this release group will depend whether the antibiotic (AT) target is intracellular or if the carrier portion represented by

j' C sX'X^X-'x'X^roX'ThrCysJ^-'CJ'jitJ³),, interferes with the activity of the antibody A_T. For example, the following three instances arc considered.

[ 0039] No Release

10040] If antibiotic A_T is capable of acting on the outer membrane or at least the periplasm of the target bacteria (e.g., polymyxin), release group R_M is likely not required. In other words, v is likely 0 in these instances. In addition, if antibiotic Ay use is limited by a systemic or renal toxicity that is expected to be mitigated by its presence in compounds of Formula I, release group RM is also likely not required. Examples of the latter include, but are not limited to, polymyxin and colistin. Thus, in certain instances, as in a thirteenth embodiment of the compounds of Formula I, v is 0 and the remaining variables for Formula I are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.

[ 0041 ] Urine Enzymes and Hydrolysis

[ 0042 ] In instances where release of the antibiotic Ay prior to , or as it reaches the bladder, but after being filtered by the glomerul i is preferred, release group R_\i is required. In other words, v is 1 in these instances. For example, segments that arc sensitive to enzymes found in the urine and produced by proximal tubular cells can be used as release group RM- Sec e.g., Bioconjugatc Chcm. 2013, Vol. 24, 29 1 -299. Hydro!yzable release groups can also be used. For example, in one instance, as in a fourteenth embodiment of the compounds of Formula I, release group RM in the compound of Formula I is -(Ci- Q,)alkyl-C(=0)-(Ci-C_c)alkyl-OC(=0)-, where the carbon atom of the carbonyl of the OC(=0)- portion is attached to antibiotic A_T, and wherein the remaining variables for Formula I arc as described above for Fonnula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[ 0043 ] Bacterial Specific Enzymes

[0044] In instances where antibiotic Ay is cleaved by a bacterial specific enzyme {e.g., bcta-lactamasc), a release group R_M that is tailored to react with the bacterial specific enzyme can used (i.e., v is 1 ). In such instances, the bacterial specific enzyme reacts release group RM and subsequent with such that antibiotic A _r is released into the target medium essentially unmodified is advantageous. In other words, the bacterial enzyme reacts with release group R_M instead of antibiotic Ay, and antibiotic Ay is subsequently released into the target medium. Exemplary release groups of this nature include, but are not limited to those which target beta-l ctamase. For example, in one instance, as in a fifteenth embodiment of the compounds of Formula I, release group RM is:

methylene indicates the point of attachment to A_T and ^vwon the NH and C(=0) indicate the point of attachment to L_R if present {or J ¹ depending on the values for w), and wherein the remaining variables for Formula I are as described above for Fomiula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

5. Description of Exemplary Antibiotics

[ 0045 ] An antibiotic AT in Formula I is an antibiotic that when bound to the remaining features of Formula I (-( v -fLH -j'CysX'x'x'X^'x'Pro 'ThrCysJ'j' ' ⁵)!), elicits an improvement in activity, a decrease in toxicity, an increase in kidney clearance, an increase in urine concentration, or a lower systemic distribution when compared to administration of the A alone, i.e., without being bound to the remaining features of Formula 1. Such antibiotics include, but are not limited to beta-lactam antibiotics, fluoroquinolone antibiotics, aminoglycosides, and others such as e.g., polymyxin, colistin, tigccyclinc, inocyclinc, and cosycyclinc. Thus, in certain instances, as in sixteenth embodiment of the compounds of Fomiula I A [ is selected from bcta-Iactam antibiotics such as meropenem, imipenem, biapenem, doripenem, meropenem, ertapenem, piperacillin, mezlocill in, temocillin, ticarcillin, carbcnicillin, ceftazidime, cefotaxime, cefaloridine, ceftriaxone, cefteram, cefpimizole, cefminox, cefalonium, and aztreonam; fluoroquinolone antibiotics such as ulifloxacin, trovafloxacin, sitailoxacon, moxifloxacin, gemifloxacin, gatifloxacin, clinafloxacin, tosufloxacin, pazufloxacin, pazufloxacin, norfloxacin, and ciprofloxacin; aminoglycosides such as kanamycin, amikacin, tobramycin, gentamicin, and neomycin; and polymyxin, colistin, tigccycline, inocyclinc, and cosycyclinc, wherein the remaining variables for Formula I are as described above for Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment. 6. Uses, Formulation, anil Administration

[ 0046] In certain embodiments, the present disclosure provides a method of treating a subject {e.g., a human) suffering from a bacterial infection, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I is such that it is an effective binding inhibitor of light chains to uromodulin. In certain embodiments, a provided composition is formulated for administration to a subject in need of such composition. In some instances, the bacterial infection is a kidney infection. In some instances, the subject being treated is also suffering from renal impairment (e.g.. acute kidney injury or myeloma cast nephropathy).

| 047] Pharmaceutically acceptable compositions arc included and can be administered to humans and other animals by other methods such as e.g. , orally, rectally, parcntcrally, intracisternally, intraperitoncally, topically (as by powders, creams, ointments, or drops), bucally, as an oral or nasal spray, or the like. In certain embodiments, the disclosed compounds may be administered parcntcrally (e.g., intravenous).

10048 ] In certain embodiments, the present disclosure also provides a method of treating a subject (e.g., a human) suffering from a bacterial, comprising administering to the subject a therapeutically effective amount of composition comprising a compound of the Formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the amount of compound of Formula I in a provided composition is such that it is an effective binding inhibitor of light chains to uromodulin. In some instances, the bacterial infection is a kidney infection. In sonic instances, the subject being treated is also suffering from renal impairment (e.g., acute kidney injury or myeloma cast nephropathy).

[ 0049] It will be understood that a specific dosage for any particular subject will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a provided compound in the composition will also depend upon the particular compound in the composition. 1_.0050] The amount of provided compounds that may be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the patient to be treated and the particular mode of administration.

EXEMPLIFICATION

1 05 1 ] Standard solid phase techniques can be employed to synthesize the disclosed compounds. For example, Fmoc (fluorenylmethyloxycarbonyl) chemistry can occurr on PEG-base Rink Amide resin, 0.45 mmol/g loading. Side-chain protection of Fmoc amino acid can include t-Bu (t-butyl) on Asp, Ser, Tyr and D-Tyr; Trt (trityl) on Asn and Cys; Boc (tcrt-butyloxycarbonyl) on Lys; Pbf (2,2,4,6,7-pcntamcthyldihydrobcnzofuranc) on Arg, Fmoc on K* (i.e., Fmoc-Lys(Fmoc)-OH can be used to coupled to the rcsin).

General Procedure for Preparation of Peptide Portion j'C sX'X^^X^^roX'ThrC sJ^^J⁴)^⁵),

1. Fmoc deprotection

10052 ] Fmoc deprotection is performed using 20% pipcridinc in DMF

(di methyl formamide) or 20% piperidine / 0.1 % 6-Cl HOBt (Hydroxybenzotriazolc) in DMF, 5min + 20 min for each deprotection.

2. Coupling of Fmoc amino acids

10053 ] Acylations are carried out using 3-fold Fmoc amino acids activated with DIC (3eq.) (Ν,Ν'-Di isopropylcarbodii mide) in the presence of 6-Cl-HOBt (3eq.). Each coupling reaction can take on average 1 -3 h for completion. Kaiser test was used throughout for the in-process control of the coupl ing completion and the Fmoc deprotection. In the case that the Kaiser test was not satisfactory, re-couplings were done using DIC/6-C1 HOBt or HCTU (2 - (6 - Chloro - 1 H - bcnzotriazolc - 1 - yl) - 1 , 1 ,3,3 - tetramethylaininium hcxafluorophosphate)/OxymaPure.

3. Resin cleavage and Peptide Recovery

10054] Peptidyl resin was extensively washed with DCM (dicloromethane) and methanol to remove the trace of DMF and dried at RT overnight. Peptidyl rcsin was cleavaged with the mixture of TFA/TIS/EDT/HiO (trifluoracctic acid/triethylsilane/1 ,2- ethanedithiol/water) (92.5/2.5/2.5/2.5, v/v/v/v) for 2.5-3 h under nitrogen bubbling. Peptides were collected by precipitation in cold diethyl cthcr/Hcxanc ( 1 / 1 , v/v). 4. Purification of Linear Peptide

1_.0055 ] Crude liner peptide was purified using Phcnomenex Gemini C- prep column. 21 .5mm x 250mm. The peptide was then dried by lyophilization..

5. Disulfide Bridge Formation

10056] Purified linear peptide was dissolved in 0.1 M ammonium bicarbonate (3- 5mg/ml), stand open to air for 2 days. Frequent HPLC testings were done to monitor the cyclization process. After cyclization, use TFA to adjust to acidic, isolated the product by lyophilization.

6. Cyclic Peptide Purification

[ 0057] Peptides were purified using the following conditions. Column: Phcnomenex Gemini, 5u, C 1 8, 1 10A, 250x21 .2mm. Mobile phase A : 0. 1 % TFA in Acctonitrilc H^O (50/50). Mobile phase B: 0.1% TFA/FhO. Gradient: 0- 100% A in 120mm. Wavelength: 229 nra. Flow rate: 16-20ml/min.

7. Isolation of Human Uromodiilin

[0058 ] Uromodulin was precipitated from fresh urine from healthy donors using 0.58M NaCL The precipitate was then washed with 0.58M NaCl and resuspended in water. The uromodulin was dialyzed extensively against water to remove salt and other contaminants (MWCo = 50 D). Samples were then stored at -20 °C without

lyophilization. Good overall purity was seen by gel electrophoresis.

8. General Binding Assays

[0059] Enzyme-l inked immunosorbent assays (EL! SA) were performed independently on the portion of the compounds of Formula I having the structure

[ 0060] Plates were coated with the following l ight chain clones overnight at 4 °C: 0.05 uM BER (subtype lambda, isolated from SP2/0 cells), 0.2 uM ROC (subtype kappa, isloatcd from CHO cells), and 0.3 uM BEN (subtype lambda, isloatcd from CHO cells). The plates were washed and treated with bovine scrum albumin (BSA) overnight at 4 °C. For peptide plates, 10 nM biotin-uromodulin was mixed with peptide overnight at 4 °C. Plates were then washed and results were revealed using strcptaviding-HRP (horseradish peroxidase) and 3,3',5,5'-tetramethylbenzidine (TMB). Results arc shown in Table 3. Table 3

Binding Inhibition (ICjo u )

SEQ I D BER BEN ROC

Sequence

No.

2 AhaCAAWDDSLNGPVCKK 500 500 500

3 AhaCnLQALRTPLYTCKK 16.0 12.0 14.9

4 AhaCLSADSSGSYLYVCKK 500 66 500

5 AhaCQVWDNSVGVCKK 500 >120 1 8.5

6 AhaCQSYDNTLSGSYVCKK > 120 1 >120

7 AhaCQSYDNTLSGSLCKK 500 500 500

8 AhaCQSYDARNV 500 58.2 500

9 AhaCQSYDHNNQ 500 26.7 500

10 AhaCQSYDSTNEGVCKK 500 500 500

11 AhaCQQSYSIPWTCKK 34.4 3.2 20.8

12 AhaCQQSYSrPYTCKK 22.9 2.5 27.3

13 AhaCQQYDSLPLTCKK 21.3 3.3 3 1 .9

14 AhaCQQYSYLPITCK*K* 17.3 2.8 20.9

15 AhaCQQYSTAPWTCKK 500 16.7 500

16 AhaCQQYYSAPPTCKK 500 14.3 >120

17 AhaCQQYKNY PWTCKK 500 7.3 >120

18 AhaCQHYDYLPITCK*K* 14.8 0.9 13.7

19 AhaCQHYGSSALTCKK 52 3.3 16.4

20 AhaCQQSYSIPWTCK*K* 60.1 2.6 nt

21 AhaCQQSYSlPYTCK*K* 49.8 nt 75.5

22 AhaCQQ*SYSIPWTCK*K* 96.9 t nt

23 AhaCQQS*YSIPWTCK*K* 54.1 nt nt

24 AhaCQQ SY* S [PWTC K*K* 67.8 nt nt

25 AhaCQQ*SYSIPYTCK*K* 35.9 nt 22.0

26 AhaCQQS*YSIPYTCK* K* 30. 1 nt 27.5

27 AhaCQQSY* SlPYTCK*K* 27. 1 2.8 26.5

28 AhaCEQSYSI PYTCKK 24.9 nt 25.2

29 AhaCQESYSIPYTCKK 26.3 nt 25.5

30 AhaCQQEYSIPYTCKK 26.5 nt 25.9 Binding Inhibition (1C₅₍₎ uM)

SEQID BER BEN ROC

Sequence

No.

31 AhaCQQSESIPYTC K 25.9 nt 24.1

32 AhaCQQSYEIPYTCKK Nt nt 28

33 AhaCQQSYSEPYTC >120 nt >12()

34 AhaCQQSYSIEYTC K >500 nt >120

35 AhaCQQSYSIPETCKK >120 nt >120

36 AhaCQQSYSIPYECKK >120 nt >500

37 AhaCRQSYSIPYTC 49.X nt 27.9

38 AhaCQRSYSIPYTC K 55 nt 26.4

39 AhaCQQRYSIPYTC 20.7 nt 22.1

40 AhaCQQSRSIPYTC K 23.5 nt 26.2

41 AhaCQQSYRIPYTC K 20.9 nt 21.6

42 AhaCQQSYSRPYTC K 27.8 nt 29.5

43 AhaCQQSYSIRYTC K >500 nt >120

44 AhaCQQSYSIPRTC K 24.9 nt 25

45 AhaCQQSYSIPYRCKX >50() nt >500

46 AhaCQQSY*SIPYTC * * *K* 23.4 nt 35.0

47 K* *CQQSY*SIPYTCK*K* 32.3 nt 33.5

48 AhaPcnQQSY*SIPYTPcnK* * 120.0 nt 120.0

49 oxCCQQSY* SIP YTCK* * 43.3 nt 41.2

50 AhaCQQYSYLPITCK*K* 17.3 nt nt

51 AhaCQQYSYLPITCR*R* 1 .6 nt nt

52 AhaCQQSYLPITCK*K* 69.0 nt nt

53 AhaCQQYSLPITC * * 120.0 nt nt

54 AhaCQQYDLPITC *K* 120.0 nt nt

55 AhaCnLQALRTPLYTCR*R* 10.6 2.0 18.1 nt = not tested

8. Ex Vivo Conditions

[00 1 ] Binding inhibition, stability, and solubility data was obtained independently on the portion of the compounds of Formula I having the structure

These results are shown in Table 4. MLO> represents the lowest [C50 at which uromodulin binding to 90% of the light ch tested was inhibited. KBB is kidney brush border enzyme.

Table 4

9. Pharmacokinetic Evaluations

10062 ] The plasma pharmacokinetics of S EQ I D No. 27 was evaluated following intravenous (IV) bolus injection (FIG. 1 ) and 2 hour IV infusion (FIG. 2) in rats. Similarly, FIG. 3 plasma pharmacokinetics of SEQ ID No. 27 following intraperitoneal injection of SEQ ID No. 27 when compared with SEQ ID No. 4 in rat. This data establishes that the portion of the compounds of Formula I having the structure j' CysX'

in particular SEQ ID No. 27, has high efficacy and very good dose-exposure proportionally over a broad range of doses.

[ 0063 ] Surprisingly, and perhaps most notably, the clearance rate of SEQ ID No. 27 was essentially equal to the glomerular filtration rate, e.g., after infusion of 10 mg/kg of SEQ ID No. 27 for 2 hours to 6 rats, the percentage of intact peptide recovered in the urine was 100% ± 22% (mean ± SD). See FIG. 4.

9. Synthesis of Peptide/Antibody Conjugates

[ 0064] Compounds of Formula I can be prepared via the following general route.

[ 0065 ] Scheme 1:

Act; Y

A b-Y- ( )>N[]-J^lCysX^lX-X-^,X⁴X³X [⁾r«X l^']ir ys.h.l'¹(.r)XP)_I

Λ,-SII - ₁₀₁

or

A-r-NH,

A_rS-Y-Ct=C)}NH-J^lCysX^lX X-ⁱX⁴X⁵X ProX'ThiCys.T-Jⁱ(J )_i(.I⁵), 102

A_T-Nn-C( ))-Y-C(=0)NH-J¹CysX¹X²X¾¹X⁵X^f L X⁷ThrCysJ²J- .T^J)_s(J⁵)_[ 1«3

[0066] As shown in scheme 1, the peptide is reacted with a compound of formula 100, where Acti and Ac are each independently carboxylic acid leaving groups such as halogen or sulfinate ester, to form an intermeidate of the formula 101. Antibody A_T comprising a thiol or amine, is then reacted with 101 to form products 102 or 103.

[0067] Exemplary compounds of Formula I made by this, or by a similar process, arc selected from:

; or a pharmaceutically acceptable salt thereof.

[0068] It will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

Claims

CLAIMS:

1. A compound of the Formula I :

A i -f RMK- LRi. -J'Cy X'x' 'X-'x'x'Pro 'TlirCysJ'j^' ^sCJ⁵).;

(I)

or a pharmaceutically acceptable salt thereof, wherein

J¹ is Aha or Arg;

X¹ to X⁷ arc each independently a natural or non-natural amino acid;

s, t, w, and v are each independently 0 or 1 ;

J² and J" are each independently Lys or Arg;

J⁴, if present is Lys or Arg;

F, if present is Lys or Arg;

L_R, if present is -C<=0)-Y-X^J;

Y is an optionally substituted linear or branched C i -Go alkyl, wherein one of more of the methylene units in the alkyl are optionally and independently replaced by O, S, NH, S(=0), S(0) , C(O), 3-pyrrolidinyl-2,5-dion- l -yl, or NHC(O);

X^a is bonded to J¹ and is -C(=0)NH- or S;

AT is an antibody.

2. The compound of Claim I , wherein X¹ is selected from Arg, Lys, His, Pro, Cys, Thr, Ser, Gin, Glu, Leu, lie, Met, Ala, Val, Gly, n-Leu, Met, Asp, and He.

3. The compound of Claim 1 or 2, wherein X¹ is selected from Arg, Gin, Glu, Leu, n- Leu, Met, Asp, and He.

4. The compound of any one of Claims 1 to 3, wherein ¹ is selected from Gin, Leu, and n-Leu.

5. The compound of any one of Claims 1 to 4, wherein X² is selected from a natural amino acid.

6. The compound of any one of Claims 1 to 5, wherein X² is selected from Scr, Thr, Cys, Met, Asn, Lys, Gin, H is, Arg, Glu, and Asp.

7. The compound of any one of Claims 1 to 6, wherei X^" is selected from Ser, Gin, His, Arg, Glu, and Asp.

8. The compound of any one of Claims 1 to 7, wherein X² is selected from Gin and His.

9. The compound of any one of Claims 1 to 8, wherein X³ is selected from a natural amino acid.

10. The compound of any one of Claims 1 to 9, wherein X ' is selected from Tyr, Trp, Phe, Scr, Thr, Cys, Met, Asn, Ala, Lys, His, Glu, Arg, and Asp.

1 1. The compound of any one of Claims 1 to 1 0, wherein X^J is selected from Tyr, Ser, Ala. Glu, Arg, and Asp.

12. The compound of any one of Claims 1 to 1 1 , wherein X ¹ is selected from Tyr, Scr, Arg, and Asp.

13. The compound of any one of Claims 1 to 12, wherein X^J is selected from a natural amino acid.

14. The compound of any one of Claims 1 to 1 3, wherein X⁴ is selected from Gly, Ala, Val, Leu, He, Pro, Phe, Tyr, Trp, Asp, Glu, Lys, Arg, and H is.

1 . The compound of any one of Claims 1 to 14, wherein X is selected from Leu, Asp, Gly, Tyr, Glu, and Arg,

16. The compound of any one of Claims 1 to 1 , wherein X⁴ is selected from Leu, Asp, Tyr, and Arg.

17. The compound of any one of Claims 1 to 16, wherein X⁵ is selected from a natural amino acid.

18. The compound of any one of Claims I to 17, wherein X³ is selected from Ser, Thr, Cys, Met, Asn, Gin, Asp, Glu, Lys, Arg, and His.

19. The compound of any one of Claims 1 to 1 8, wherein X' is selected from Tyr, Scr, Arg, Glu, and Asp.

20. The compound of any one of Claims 1 to 19, wherein X^s is selected from Gly, Ala, Val, Leu, lie, Pro, Phe, Tyr, Trp, Scr, Cys, Met, Gin, Lys, Arg, and His.

21 . The compound of any one of Claims 1 to 20, wherein X⁶ is selected from He, Leu, Pro, Val. Ala, Gly, His, Lys, and Arg.

22. The compound of any one of Claims 1 to 21 , wherein X^fi is selected from lie. Leu, and Arg.

23. The compoundof any one of Claims 1 to 22, wherein X^fi is selected from He and Leu.

24. The compound of any one of Claims I to 23, wherein X⁷ is selected from Gly, Ala, Val, Leu, He, Pro, Phe, Tyr, Trp, Ser, Thr, Cys, Met, Asn, Gin, Lys, Arg, and His.

25. The compound of any one of Claims 1 to 24, wherein X⁷ is selected from Tyr, Phe,

26. The compound of any one of Claims 1 to 25, wherein X⁷ is selected from Tyr, Arg, and Tip.

27. The compound of any one of Claims 1 to 26, wherein X⁷ is Tyr.

28. The compound of any one of Claims 1 to 27, wherein s and ι arc each 0.

29. The compound of any one of Claims 1 to 28, wherein s and t arc each 1.

30. The compound of any one of Claims 1 to 29, where J¹ is Aha.

31. The compound of Claim I , wherein the peptide is selected from

AhaCQQSYSIPWTCK ;

AhaCQQSYSIPYTCK ;

AhaCQQYDSLPLTCKK;

AhaCQQYSYLPITC .* .*;

AhaCQQYSTAPWTC ;

AhaCQQYYSAPPTCKK;

AhaCQQYKNYPWTCK ;

AhaCQHYDYLPlTC * *;

AhaCQQSYSIPWTCK*K*;

AhaCQQSYSIPYTCK*K*;

AhaCQQ*SYSIPWTC *K*;

AhaCQQS*YSIPWTC * *;

AhaCQQSY*SIPWTC *K*;

AhaCQQ*SYSIPYTC *K*;

AhaCQQS*YSIPYTCK*K*:

AhaCQQSY*SIPYTC * *; AhaCEQSYSIPYTCKK;

AhaCQESYSIPYTCKK;

AhaCQQEYSrPYTCK ;

AhaCQQSESIPYTC K;

AhaCQQSYEIPYTC ;

AhaCQQSYSEPYTCKK;

AhaCQQSYSIEYTCKK;

AhaCQQSYSIPETCK ;

AhaCQQSYSIPYEC ;

AhaCRQSYSIPYTC K;

A haCQRSY SI PYTCKK ;

AhaCQQRYSlPYTCK ;

AhaCQQSRSIPYTC ;

AhaCQQSYRIPYTCKK;

AhaCQQSYSRPYTC K;

AhaCQQSYSIRYTCK ;

AhaCQQSYSIPRTCKK;

AhaCQQSYSIPYRC K;

AhaCQQSY*SIPYTCK*K* *K*;

AhaCQQYSYLPITCK* *;

AhaCQQYSYLPlTCR*R*;

AhaCQQS YLP.TCK*K* ;

AhaCQQYSLPITCK*K*;

AhaCQQYDLPITCK* *: and

AhaCQQSYSIPYTCR*R*;

or a pharmaceutically acceptable salt thereof.

32. The compound of any one of Claims 1 to 31, wherein Y is an optionally substituted linear or branched G-Go alkyl, wherein one of more of the methylene units in the alkyl are optionally and independently replaced by O, NH, S, C(=0), 3-pyrrolidinyl-2,5-dion-l- yl,orNHC(=0).

33. The compound of any one of Claims 1 to 32, wherein Y is an optionally substituted linear or branched Ci-C io alky], wherein one of more of the methylene units in the alkyl arc optionally and independently replaced by NH, C(=0), 3-pyrrolidinyI-2,5-dion- l -yl, or N HC(O).

34. The compound of any one of Claims 1 to 33, wherein Y is an optionally substituted linear or branched C_J -C K, alkyl, wherein one of more of the methylene units in the alkyl arc optionally and replaced by 3-pyrrolidinyl-2,5-dion- l -yl or NHC(=0).

35. The compound of any one of Claims 1 to 34, wherein Y is a linear or branched Q- Ci alkyl, wherein one of the methylene units in the alkyl is replaced by 3-pyrrolidinyl- 2,5-dion- l-yl or NHC(=0).

36. The compound of any one of Claims 1 to 35, wherein Y is a linear C j-Cr, alkyl, wherein one of the methylene units is optionally replaced by 3-pyrrolidinyl-2,5-dion- l -yl or NHC(=0).

37. The compound of any one of Claims 1 to 36, wherein RM is -(CrCr_s)alkyl-C(=0)- {C

portion is attached to A*.

methylene indicates the point of attachment to Ay and ./wvon the NH and C(=0) indicate the point of attachment to LR if present.

39. The compound of any one of Claims 1 to 36, wherein v is 0.

40. The compound of any one of Claims 1 to 39, wherein w is 1 .

41 . The compound of any one of Claims 1 to 40, wherein AT is selected from meropenem, imipenem, biapenem, doripencm, mcropencm, ertapenem, piperacillin, mezlocillin, temoci llin, ticarci llin, carbenicillin, ceftazidime, cefotaxime, ccfaloridinc, ceftriaxone, ccfteram, cefpimizole, cefminox, ccfalonium, aztrconam, ulifloxacin, trovafloxacin, sitafloxacon, moxifloxacin, gemifloxacin, gatifloxacin, clinafloxacin, tosufloxacin, pazufloxacin, pazufloxacin, norfloxacin, ciprofloxacin, kanamycin, amikacin, tobramycin, gcntamicin, neomycin, polymyxin, colistin, tigccyclinc, inocyclinc, and cosycyclinc.

; or a pharmaceutically acceptable salt thereo

43. A pharmaceutical composition comprising a peptide of any one of Claims 1 to 42, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable earner.

44. A method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a peptide of any one of Claims 1 to 42, or a pharmaceutically acceptable salt thereof.

45. The method of Claim 44, wherein the bacterial infection is a kidney infection.

46. The method of Claim 44 or 45, wherein the subject is futhcr suffering from renal impairment.