Lipopeptides as antibacterial agents

1. A compound having the formula (I):

and salts thereof,

wherein R is:

wherein each of X and X″ is independently C═O, C═S, C═NH, C═NR X , S═O or SO 2 ;

wherein R X is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;

wherein B is X″R Y , H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;

wherein R Y is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;

wherein A is alkyl, alkenyl, alkynyl, alkoxy or aryloxy;

provided that when B is H and X is C═O, then A is other than

(a) —(C 1 -C 16 unsubstituted alkyl)-NH 2 ;

(b) —(C 1 -C 10 unsubstituted alkyl)-NHC(O)R D , wherein R D is (C 1 -C 17 ) unsubstituted alkyl or (C 2 -C 17 ) unsubstituted alkenyl;

(c) —(C 1 -C 18 )-unsubstituted alkyl;

(d) —(C 1 -C 18 )-selected substituted alkyl wherein one proton is replaced by a hydroxyl, carboxyl, or C 1 -C 3 alkoxy, or one to three protons is replaced by a halo substituent;

(e) —(C 4 -C 18 )-unsubstituted alkenyl;

wherein R 54 is C 1 -C 17 -unsubstituted alkyl or C 2 -C 17 -unsubstituted alkenyl; wherein R 55 is hydroxyethyl, hydroxymethyl, mercaptomethyl, mercaptoethyl, methylthioethyl, 2-thienyl, 3-indolemethyl, phenyl optionally substituted with a halo, nitro, C 1 -C 3 -unsubstituted alkyl, hydroxy, C 1 -C 3 -unsubstituted alkoxy, C 1 -C 3 -unsubsituted alkylthio, carbamyl or C 1 -C 3 unsubstituted alkylcarbamyl; or benzyl optionally substituted with a halo, nitro, C 1 -C 3 -unsubstituted alkyl, hydroxy, C 1 -C 3 -unsubstituted alkoxy, C 1 -C 3 -unsubsituted alkylthio, carbamyl or C 1 -C 3 unsubstituted alkylcarbamyl; wherein t is 0 or 1 and wherein u is an integer from 1-3;

when B is H, X together with A is other than 8-methyldecanoyl, 10-methyldodecanoyl, 10-methylundecanoyl, decanoyl, or dodecanovi; and

when B is H and X is C═O, then X, together with A, does not form a carbamate amino protecting group; and

wherein R 1 is

wherein each of X′ and X′″ is independently C═O, C═S, C═NH, C═NR X ′, S═O or SO 2 ;

wherein m is 0 or 1;

wherein R X ′ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;

wherein B′ is X′″R Y ′, H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;

wherein R Y ′ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;

wherein A′ is H, NH 2 , NHR A ′, NR A ′R B ′, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl or heterocyclyl;

wherein each of R A ′ and R B ′ is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;

wherein when m is 0, then A′ is additionally:

wherein each of R 50 —R 53 is independently C 1 -C 15 alkyl;

alternatively, wherein B′ and A′ together form a 5-7 membered heterocyclic or heteroaryl ring; and

wherein R 2 is

wherein K and K′ together form a C 3 -C 7 cycloalkyl or heterocyclyl ring or a C 5 -C 10 aryl or heteroaryl ring;

wherein J is H, amino, NHR J , NR J R K , alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, hydroxyl, thio, alkylthio, alkenylthio, sulfinyl, sulfonyl, azido, cyano, halo,

wherein each of R 24 , R 25 , and R 26 is independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or R 24 and R 25 together form a 5-8 membered heterocyclyl ring;

wherein each of R J and R K is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; or

alternatively, wherein J, together with R 17 , forms a 5-8 membered heterocyclyl or cycloalkyl ring; or

alternatively, wherein J, together with both R 17 and R 18 , forms a 5-8 membered aryl, cycloalkyl, heterocyclyl or heteroaryl ring;

wherein each of R 17 and R 18 is independently H, halo, hydroxyl, alkoxy, amino, thio, sulfinyl, sulfonyl or

alternatively wherein R 17 and R 18 taken together form a ketal, thioketal,

wherein each of R 22 and R 23 is independently H or alkyl.

2. A compound having the formula (I):

and salts thereof;

wherein R is:

wherein each of X and X″ is independently C═O, C═S, C═NH, C═NR X , S═O or SO 2 ;

wherein R X is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;

wherein B is X″R Y , H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;

wherein R Y is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;

wherein B and A together form a 5-7 membered heterocyclic or heteroaryl ring; and

wherein R 1 is

wherein each of X′ and X′″ is independently C═O, C═S, C═NH, C═NR X ′, S═O or SO 2 ;

wherein m is 0 or 1;

wherein R X ′ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;

wherein B′ is X′″R Y ′, H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;

wherein R Y ′ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;

wherein A′ is H, NH 2 , NHR A ′, NR A ′R B ′, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl or heterocyclyl;

wherein each of R A ′ and R B ′ is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;

wherein when m is 0, then A′ is additionally:

wherein each of R 50 -R 53 is independently C 1 -C 15 alkyl;

alternatively, wherein B′ and A′ together form a 5-7 membered heterocyclic or heteroaryl ring; and

wherein R 2 is

wherein K and K′ together form a C 3 -C 7 cycloalkyl or heterocyclyl ring or a C 5 -C 10 aryl or heteroaryl ring;

wherein J is H, amino, NHR J , NR J R K , alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, hydroxyl, thio, alkylthio, alkenylthio, sulfinyl, sulfonyl, azido, cyano, halo,

wherein each of R 24 , R 25 , and R 26 is independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or R 24 and R 25 together form a 5-8 membered heterocyclyl ring;

wherein each of R J and R K is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; or

alternatively, wherein J, together with R 17 , forms a 5-8 membered heterocyclyl or cycloalkyl ring; or

alternatively, wherein J, together with both R 17 and R 18 , forms a 5-8 membered aryl, cycloalkyl, heterocyclyl or heteroaryl ring; and

wherein each of R 17 and R 18 is independently H, halo, hydroxyl, alkoxy, amino, thio, sulfinyl, sulfonyl or

alternatively, wherein R 17 and R 18 taken together form a ketal, thioketal,

wherein each of R 22 and R 23 is independently H or alkyl.

3. The compound according to claim 1 , wherein R is:

wherein each of R 3 , R 4 R 5 , and R 6 is independently H, alkyl, aryl, heterocyclyl or heteroaryl, wherein R 44 is alkyl, aryl, heterocyclyl or heteroaryl and wherein R 200 is alkyl.

4. The compound according to claim 3 , wherein R is

wherein R 4 ′ is aryl-substituted alkyl, optionally substituted (C 8 -C 14 )-straight chain alkyl or

wherein R 7 is an alkyl group.

5. The compound according to claim 4 , wherein R is

wherein X 3 is chloro or trifluoromethyl.

6. The compound according to either of claims 1 or 2 , wherein R 1 is:

wherein R 8 is a natural amino acid side chain or an amino acid side chain;

wherein each of R 9 , R 10 and R 11 is independently H, alkyl, aryl, heterocyclyl or heteroaryl;

wherein R 12 is heterocyclyl, heteroaryl, aryl, or alkyl and

wherein R 13 is (C 1 -C 3 -alkyl) or aryl.

7. The compound according to claim 6 , wherein R 1 is:

wherein R 8 is tryptophan side chain or lysine side chain;

wherein each of R 10 and R 11 is independently H or alkyl;

wherein R 12 is imidazolyl, N-methylimidazolyl, indolyl, quinolinyl, benzyloxybenzyl, or benzylpiperidenylbenzyl; and

wherein X 4 is fluoro, or trifluoromethyl.

8. The compound according to either of claims 1 or 2 , wherein J is H, amino, azido or

wherein R 17 and R 18 taken together form a ketal,

or wherein R 17 is hydroxyl when R 18 is H;

or wherein J, together with R 17 , forms a heterocyclyl ring.

9. The compound according to claim 8 , wherein R 2 is:

wherein R 17 and R 18 taken together are:

wherein R 22 is H or alkyl; and wherein R 19 is H, amino, azido or

10. The compound according to claim 9 , wherein R 2 is

11. The compound according claim 1 wherein said compound is selected from

Cpd

#

R

R 1

R 2

6

8

NHCO(CH 2 ) 8 CO 2 CH 3

9

NHCO(CH 2 ) 6 CO 2 CH 3

10

NHCO(CH 2 ) 6 NHBoc

11

NHCO(CH 2 ) 7 NHBoc

12

NHCO(CH 2 ) 10 NHBoc

13

NHCO(CH 2 ) 11 NHBoc

18

NH 2

19

NH 2

20

21

22

23

24

25

34

35

36

40

NH 2

41

NHBoc

43

NHBoc

44

NHBoc

49

NH 2

50

100

NH 2

106

115

NHBoc

116

NH 2

123

NHCOCH 2 S(CH 2 ) 11 CH 3

NH 2

124

NHCOCH 2 S(CH 2 ) 10 CH 3

NH 2

125

NHCOCH 2 S(CH 2 ) 9 CH 3

NH 2

12. The compound of claim 11 wherein said compound is

Cpd

#

R

R 1

R 2

18

NH 2

13. A pharmaceutical composition comprising the compound according to either of claims 1 or 2 and a pharmaceutically acceptable carrier.

14. A method of treating a bacterial infection in a subject, comprising the step of administering a therapeutically-effective amount of the pharmaceutical composition according to claim 13 to a subject in need thereof for a time and under conditions effective to ameliorate said bacterial infection.

15. The method according to claim 14 , wherein said subject is a human, an animal, a cell culture or a plant.

16. The method according to claim 14 , wherein said bacterial infection is caused by a gram-positive bacteria.

17. The method according to claim 16 , wherein said bacteria is an antibiotic-resistant bacteria that is resistant to an antibiotic that is not included within the scope of Formula (I).

18. The method according to claim 17 , wherein said antibiotic-resistant bacteria are resistant to an antibiotic selected from vancomycin, methicillin, glycopeptide antibiotics, penicillin or daptomycin.

19. The method according to claim 14 , further comprising the step of co-administering more than one compound of Formula (I) according to either of claims 1 or 2 to a subject in need thereof.

20. The method according to claim 14 , further comprising the step of co-administering a second antimicrobial agent wherein said second antimicrobial agent is not included within the scope of Formula (I).

21. The method according to claim 20 , wherein said second antimicrobial agent is selected from penicillins, carbapenems, cephalosporins, aminoglycosides, bacitracin, gramicidin, mupirocin, chloramphenicol, thiamphenicol, fusidate sodium, lincomycin, clindamycin, macrolides, novobiocin, polymyxins, rifamycins, spectinomycin, tetracyclines, vancomycin, teicoplanin, streptogramins, anti-folate agents, trimethoprim, pyrimethamine, nitroimidazoles, quinolones, fluoroquinolones, isoniazid, ethambutol, pyrazinamide, para-aminosalicylic acid (PAS), cycloserine, capreomycin, ethionamide, prothionamide, thiacetazone, viomycin, everninomicin, glycopeptide, glycylcycline, ketolides, oxazolidinones, imipenen, amikacin, netilmicin, fosfomycin, gentamicin, ceftriaxone, ZIRACIN (56-deacetyl-57-demethyl-45-O-de(2-methyl-1-oxopropyl)-12-O-(2,3,6-trideoxy-3-C-methyl-4-O-methyl-3-nitro-alpha-L-arabino-hexopyranosyl)flambamycin), LY333328 (oritavancin), linezolid (N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide), SYNERCID (dalfopristin-quinupristin), aztreonam (2-[[(Z)-[1-(2-amino-4-thiazolyl)-2-[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methyl-propanoic acid), metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol), epiroprim (5-[[3,5-diethoxy-4-(1H-pyrrol-1-yl)phenyl]methyl]-2,4-pyrimidinediamine), OCA-983 (1-[[(2S)-2-amino-3-methyl-1-oxobutyl]amino]-2,5-anhydro-3-S-[(4R,5S,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]-1,4-dideoxy-3-thio-D-threo-pentitol), GV-143253 (trinem), sanfetrinem ((1S, 5S, 8aS, 8bR)-1, 2, 5, 6, 7, 8, 8a, 8b-octahydro-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-azeto[2,1-a]isoindole-4-carboxylic acid), CS-834 ((4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-oxo-3-pyrrolidinyl]thio]-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid (2,2-dimethyl-1-oxopropoxy)methyl ester), biapenem (6-[[(4R,5S,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium inner salt), KA 159 (stipiamide), dynemicin A((1S,4R,4aR, 14S,14aS,18Z)-1,4,7,12,13, 14-hexahydro-6,8,11-trihydroxy-3-methoxy-1-methyl-7,12-dioxo-4a, 14a-epoxy-4,14-[3]hexene[1,5]diynonaphtho[2,3-c]phenanthridine-2-carboxylic acid), DX8739 ((4R,5S,6S)-3-[[(3S,5S)-5-[[4-[(2S)-5-amino-2-hydroxy-1-oxopentyl]-1-piperazinyl]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), DU 6681 ((4R,5S,6S)-3-[[(6S)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), cefluprenam ((2E)-N-(2-amino-2-oxoethyl)-3-[(6R,7R)-7-[[(2Z)-(5-amino-1,2,4-thiadiazol-3-yl)[(fluoro methoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]-N-ethyl-N-methyl-2-propen-1-aminium inner salt), ER 35786 ((4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[[(3S,5S)-5-[(R)-hydroxy(3R)-3-pyrrolidinylmethyl]-3-pyrrolidinyl]thio]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrochloride), cefoselis((6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(methoxy imino)acetyl]amino]-3-[[2,3-dihydro-2-(2-hydroxyethyl)-3-imino-1H-pyrazol-1-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid), sanfetrinem celexetil ((1S,5S,8aS,8bR)-1,2,5,6,7,8,8a,8b-octahydro-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-azeto[2,1-a]isoindole-4-carboxylic acid 1-[(cyclohexyloxy)carbonyl]oxy]ethyl ester), cefpirome (1-[[(6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-6,7-dihydro-5H-cyclopenta[b]pyridinium inner salt), HMR-3647 (3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)oxy]-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl[[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]imino]]-erythromycin), RU-59863 (C-7 catechol substituted cephalosporin), KP 736 ((6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)[[(1,4-dihydro-1,5-dihydroxy-4-oxo-2-pyridinyl)methoxy]imino]acetyl]amino]-8-oxo-3-[(1,2,3-thiadiazol-5-ylthio)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt), Rifalazil (1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-[4-(2-methylpropyl)-1-piperazinyl]-1-oxo-rifamycin VIII), MEN 10700 ((5R,6S)-3-[[(2-amino-2-oxoethyl)methylamino]methyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), lenapenem ((4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[[(3S,5S)-5-[(1R)-1 hydroxy-3-(methylamino)propyl]-3-pyrrolidinyl]thio]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), BO 2502A ((4R,5S,6S)-3-[(2S,3′S,4S)-[2,3′-bipyrrolidin]-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), NE-1530 (3′-sialyllacto-N-neotetraose), K130 (5-[[4-[3-[[4-[(4-aminophenyl)sulfonyl]phenyl]amino]propoxy]-3,5-dimethoxyphenyl]methyl]-2,4-pyrimidinediamine), PD 138312 ((R)-7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid), PD 140248 (7-[(3R)-3-[(1S)-1-aminoethyl]-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid), CP 111905 (5-deoxy-5-[[(2E)-3-[3-hydroxy-4-(2-propenyloxy)phenyl]-2-methyl-1-oxo-2-propenyl]amino]-1,2-O-methylene-D-neo-inositol), sulopenem ((5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(1R,3S)-tetrahydro-1-oxido-3-thienyl]thio]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), ritipenam acoxyl ((5R,6R)-3-[[(aminocarbonyl)oxy]methyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (acetyloxy)methyl ester), RO-65-5788 ((6R,7R)-7-[[(2Z)-(5-amino-1,2,4-thiadiazol-3-yl)(hydroxyimino)acetyl]amino]-3-[(E)-[(3′R)-1′-[[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy]carbonyl]-2-oxo[1,3′-bipyrrolidin]-3-ylidene]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt), Sch-40832 (N-[[48-[1-[[2,6-dideoxy-3-O-(2,6-dideoxy-D-arabino-hexopyranosyl)-D-arabino-hexopyranosyl]oxy]ethyl]-15-ethylidene-1,3a,4,5,10,11,12,13,14,15,19,20,21,22,28, 29,41,42-octadecahydro-41-hydroxy-12,45-bis(1-hydroxyethyl)-1-(hydroxymethyl)-22-(1-hydroxy-1-methylpropyl)-36-methyl-51,54,57-tris(methylene)-3-(methylthio)-10,13,20,27,38,49,52,55,58-nonaoxo-18H,27H-5a,29-(iminoethaniminoethanimino ethaniminoethanimino[7,2]quinolinomethanoxy methano)-9,6:19,16:26,23:33,30-tetranitrilo-16H,33aH-imidazo[1′,5′:1,6]pyrido [3,2-m][1,11,17,24,4,7,20, 27]tetrathiatetraazacyclotriacontin-1-yl]carbonyl]-2,3-didehydroalanyl-2,3-didehydro-alanine methyl ester stereoisomer), micacocidin A ((OC-6-26-A)-[(4S)-2-[(2S)-2-[(2R,4R)-2-[(4R)-4,5-dihydro-2-[2-(hydroxy-.kappa.O)-6-pentylphenyl]-4-thiazolyl-.kappa.N3]-3-methyl-4-thiazolidinyl-.kappa.N3]-2-(hydroxy-.kappa.O)-1,1-dimethylethyl]-4,5-dihydro-4-methyl-4-thiazolecarboxylato(2-)-.kappa.N3, .kappa.O4]-Zinc), SR-15402 ((1S,5S,8aS,8bR)-1,2,5,6,7,8,8a,8b-octahydro-1-[(1R)-1-hydroxyethyl]-2-oxo-5-[(3S)-3-pyrrolidinylthio]-azeto[2,1-a]isoindole-4-carboxylic acid TOC 39 (1-(2-amino-2-oxoethyl)-4-[[(1E)-2-[(6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl) (hydroxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]ethenyl]thio]-pyridinium inner salt), carumonam ([[(Z)-[2-[[(2S,3S)-2-[[(aminocarbonyl)oxy]methyl]-4-oxo-1-sulfo-3-azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]oxy]-acetic acid), cefozopran (1-[[(6R,7R)-7-[[(2Z)-(5-amino-1,2,4-thiadiazol-3-yl)(methoxy imino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-imidazo[1,2-b]pyridazinium inner salt), cefetamet pivoxil ((6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(methoxy imino)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (2,2-dimethyl-1-oxopropoxy)methyl ester), or T 3811 (des-F(6)-quinolone).

22. The method according to claim 20 , wherein said antimicrobial agent is selected from imipenen, amikacin, netilmicin, fosfomycin, gentamicin, ceftriaxone, teicoplanin, ZIRACIN (56-deacetyl-57-demethyl-45-O-de(2-methyl-1-oxopropyl)-12-O-(2,3,6-trideoxy-3-C-methyl-4-O-methyl-3-nitro-alpha-L-arabino-hexopyranosyl)flambamycin), LY333328 (oritavancin), HMR-3647 (3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)oxy]-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl[[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]imino]]-erythromycin), linezolid (N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide), SYNERCID (dalfopristin-quinupristin), aztreonam (2-[[(Z)-[1-(2-amino-4-thiazolyl)-2-[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methyl-propanoic acid), or metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol).

23. The method according to claim 15 , wherein said subject is a human or an animal.

24. The method according to claim 23 , wherein said subject is a human.

25. The compound of claim 1 having the formula (II):

wherein R 14 is selected from the group consisting of

wherein R 56 is an optionally substituted straight-chain C 8 -C 14 alkyl group and wherein q′ is 1-3.

26. The compound according to claim 25 , wherein said compound is selected from:

Compound #

R 14

45

37

46

38

47

39

27. A compound having the formula (I′):

and salts thereof; wherein R 100 , R 101 and R 102 are selected from:

Cpd

#

R 100

R 101

R 102

72

NHBoc

73

NHBoc

74

NHBoc

109

NHCOCHCH(CH 2 ) 7 CH 3

NHBoc

110

NHCOCHCH(CH 2 ) 9 CH 3

NHBoc

111

NHCOCHCH(CH 2 ) 7 CH 3

NH 2

112

NHCOCHCH(CH 2 ) 9 CH 3

NH 2

28. The method according to claim 20 , wherein the second antimicrobial agent is a synthetic antibacterial selected from nitrofurans, methenamine mandelate or methenamine hippurate.