AU2003266863B2

AU2003266863B2 - Carbohydrate based anti-bacterials

Info

Publication number: AU2003266863B2
Application number: AU2003266863A
Authority: AU
Inventors: Giovani Abbenante; George Adamson; Bernd Becker; Matthias Grathwohl; Giang Le Thanh; Wim Meutermans; Premraj Rajaratnam; Gerald Tometzki
Original assignee: Vast Bioscience Pty Ltd
Current assignee: Vast Bioscience Pty Ltd
Priority date: 2002-10-17
Filing date: 2003-10-16
Publication date: 2007-03-08
Anticipated expiration: 2023-10-16
Also published as: AU2003266863A1

Description

WO 2004/035062 PCT/AU2003/001377 CARBOHYDRATE BASED ANTI-BACTERIALS FIELD OF THE INVENTION The invention relates to disaccharide compositions that have antibacterial properties.

BACKGROUND OF THE INVENTION Bacteria have a great ability to generate resistance to drugs through lateral gene transfer, mutation of enzymes, or by expressing enzymes which actively pump out the drug or break it down. Over the past 10 years resistance to existing drugs has become a significant problem in many countries. No new antibacterial drugs have been developed over the past 15 years. Vancomycin is currently the drug of last resort to combat the multidrug resistant Gram-positive bacteria. In many places vancomycin-resistant Staphylococcus aureus and Enterococci (VRE) have been discovered. There is thus a desperate need for a new antibacterial drug to replace the drug of last resort.

There are a host of cytoplasmic targets for the development of new antibacterials, such as gyrase inhibitors, protein synthesis inhibitors, muramyl cascade inhibitors and many more. The major hurdle in designing such drugs is that in addition to enzyme based activity these drugs need to cross the bacterial cell wall to exert their antibacterial effect. On the other hand, enzymes involved in the stage III synthesis of the bacterial cell wall exist on the cell wall exterior, and therefore drugs inhibiting these enzymes can exert their bactericidal or bacteriostatic effect without having to cross the cell wall. Penicillin, cephalosporin and vancomycin are drugs that act on the transpeptidase enzymes which control the final steps in the peptidoglycan biosynthesis. Moenomycin is known to act on the transglycosylase enzymes, which are similarly involved in the polymerization of disaccharide precursors. Moenomycin displays very high potency at MIC level, and is used in animal feed as a growth promoter.

Moenomycin is a lipid-linked pentasaccharide. Through extensive SAR experiments it was realised that smaller fragments of moenomycin were capable of exerting antibacterial activity. Trisaccharide fragments of moenomycin still display antibacterial activity, but are not sufficiently stable to be useful drugs. On the basis of this, Sofia and coworkers discovered a new series of disaccharides, carrying aromatic WO 2004/035062 PCT/AU2003/001377 2 substituents in well defined positions around the disaccharide, which displayed significant MIC activity [W00064915 and W09926596].

A further class of disaccharide molecules, based on a sub-structure of vancomycin was shown to have antibacterial activity against vancomycin resistant bacteria. This class of molecules was subsequently demonstrated to contain transglycosylase inhibitors, and were not transpeptidase inhibitors as is vancomycin itself [W09853813].

SUMMARY OF THE INVENTION The present invention is directed to antibacterial compositions and is especially directed to a method of reducing bacterial growth by contacting bacteria with particular disaccharide like moieties.

The present invention may also be directed to an antibacterial pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one particular disaccharide like moiety.

The present invention may also be directed to a method of screening such compounds for anti-bacterial activity by contacting the compounds with a Grampositive or Gram-negative bacteria and monitoring the growth or growth inhibition of the bacteria.

In a first aspect, the invention provides a method of inhibiting bacterial growth by contacting a bacteria with at least one disaccharide compound of General Formula I, W U Z R2

R

4

R

3 General Formula I Wherein the pyranose rings may be of any configuration, T is either R or -XR, where X is defined as oxygen, sulphur, NHC(O)-, and wherein R is selected from the non-limiting set comprised of H, or an alkyl, alkenyl, alkynyl, WO 2004/035062 WO 204/05062PCT/A1J20031001377 3 heteroalkyl, aryl, heteroaryl, arylalkcyl or heteroarylalkyl of 1 to 20 atoms which is optionally substituted, and can be branched or linear. Typical substituents include but are not limited to OH, NO, NO 2

NH

2

N

3 halogen, CF 3

CHF

2

CH

2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, amninoalkyl, aminodialkyl, aminotrialkyl, amninoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, amninoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted, U and Z independently selected from. OR, NUR, NR(R) (where R may be the same or different), or the following non-limiting set, S 0 NH 0 0 AN 1 KN'R 0'R AN' k N R NKN'R ,N R H H H H H H H H NH N' Ro

S

/N SR AN 1 R A IR N KSR H H H

H

0 S 00 11 N SR OR H-N-S-R -0-S-R H H H6 a11 R H H 0 0 0

A

KAI NOA HO HO __IH HORNA HOR 0~ 0 RH R R ,0R R' H R1 and R 2 are independently selected ftrm H, CH 3

CH

2 XR, and C(O)NHR, W and W 4 are independently selected from H, OH, OR, NHCOR, and W is independently selected from ORL, NHRL, NRLR, or the following the following non-limiting set, WO 2004/035062 PCT/AU2003/001377 4 S NH 0 0 N NRL/N ,RL R L N N-RL.N RL H H H H H H H H NH N O S N S R L N- 'NRL O OI RL -N SRL H H H H

O

0 s 0 0o 1 iN SRL /N ORL -N--RL O-S-RL O N H H H 0 R

L

0 0 0 0 0 O O O O O 11 II II II II HO P-N A HO OA HO A HO-'y" HO PN R- H RLO RL/O RL H Wherein R L is a substituted or unsubstituted, linear or branched, saturated or unsaturated C3 to C55 alkyl, heteroalkyl, arylalkyl, alkylaryl chain. Substituents may include but are not limited to acidic groups such as carboxylic acids, sulfonic acids, phosphoric acids, tetrazoles, or other carboxylic acid mimetics or basic groups such as amines, guanidines, amidines, imidazoles or other amine mimetics In a further aspect, the invention provides a method of inhibiting bacterial growth by contacting a bacteria with at least one disaccharide compound of General Formula II,

R

4 ,O A W "'U 0o Z CH 2

OH

HO OH General Formula II Wherein the disaccharide linkage is alpha or beta, A is defined as hydrogen, OR or SR, and R, U, W, Z and R 4 are defined as in General Formula I.

WO 2004/035062 PCT/AU2003/001377 In a more preferred aspect, the invention provides a method of inhibiting bacterial growth by contacting a bacteria with at least one disaccharide compound of General Formula III,

R

4 0 A O0 RL) N H 0 Z -CH 2 0H HO OH General Formula III Wherein A is defined as in General Formula I, and U, Z, R L and R 4 are defined as in General Formula I.

The bacterial may be Gram-positive or Gram-negative bacteria. The bacteria may comprise an E-coli bacteria, a Staphylococci Bacteria such as Staphylococcus aureus, or other bacteria such as Micrococcus luteus (ATCC272), Staphylococcus aureus (ATCC29213), Staphylococcus aureus (ATCC43300) MRSA, Enterococcus faecalis (ATCC29212), Enterococcus faecalis (ATCC51299) Vancomycin resistant and Streptococcus pyogenes (ATCC8668).

The method may comprise administering an effective amount of a 2 0 compound of the first aspect, to a subject in need of such treatment. The subject may be a human, or may be a domestic, companion or zoo animal.

In another form, the invention may reside in an antibacterial composition comprising at least one compound as described above. The composition may comprise a pharmaceutical composition.

The compounds of the invention may be mixed with a pharmaceutical acceptable carrier, adjuvant, or vehicle which may comprise a-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.

WO 2004/035062 PCT/AU2003/001377 6 The pharmaceutical derivative may comprise a salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention, although no limitation is meant thereby.

Compounds of the invention may be administered orally such as by means of a tabled, powder, liquid, emulsion, dispersion and the like; by inhalation; topically such as by means of a cream, ointment, salve etc; and as a suppository, although no limitation is meant thereby.

Methods and pharmaceutical carriers for preparation of pharmaceutical compositions are well known in the art, as set out in textbooks such as Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Company, Easton, Pennsylvania, USA.

It will be clearly understood that, if a prior art publication is referred to herein, this reference does not constitute an admission that the publication forms part of the common general knowledge in the art in Australia or in any other country.

BEST MODE MIC testing: The broth microdilution format of the National Committee for Clinical Laboratory Standards (NCCLS) approved standard for susceptibillity tests as outlined in M7-A4 "methods for dillution Antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard fifth edition", January 2000 was utilized for minimum inhibitory concentration testing in Mueller-Hinton broth. The broth for Streptococcus pyogenes testing was supplemented with 2% laked horse blood. A positive result in initial testing was determined by complete inhibition of macroscopic bacterial growth at a concentration of 128 micrograms per mL after incubation for 16 to 24 hours at 37 degrees C. In the case of Micrococcus luteus, incubation was at degrees C.

WO 2004/035062 WO 204105062PCTiAU2003!001377 Example 1 R2 OH NHOH HO3 00 HO 0 /NH

NH

2

RI

IComp. No. RiI R2 IMassIli R, SA24[S48EC4 1 A5 A9 1679 14.62 n.d. I-1 In all examples, indicates an MIC value of less than 128 micrograms per mL, indicates an MIC of greater then 128 micrograms per mL and n.d. indicates not determined.

Bacterial Types are: SA24 S. aureus after 24 hours exposure SA48 S.aureus after 48 hours exposure EC24 E. coli after 24 hours exposure Example 2 -Comp. No. n X IY R2 R3 MS R 1 SA24 SA48 EC24 2 -1 Al A10OAll A7 875 n.d 3 1 Al1AlO A4 A9 831 n.d 4 0 Al AlO A12. A9 800 .5.1 d 0 Al AlO A5 A7 862 4.92 6 0 'Al 'AlO A5 A9 851 5.36 nad n.d.

7 1 JAlO1Al A5 A7 876 5.01 WO 2004/035062 WO 204/05062PCT/A1J20031001377 8 ExaMple 3 OH R\NH OH HO 0

HO

R2N/H

O<NH

Comp. No. R2 R3 MW Rf SA24 SA48 EC24 I 8 A5 A7 824 4.72 +F 9 A5 A9 813 5.56 n.d. n.d.

WO 2004/035062 WO 204/05062PCT/A1J20031001377 Example 4 OH R\NH OH

HOH

x y SA2 EC2 Comp. No. X YV R2 R3 MW Rf A SA48 44 Al AlO A12 A7 875 n.d. 11 Al A10 A4 A9 831 5.18 +I 12 Al A10 A4 A7 843 4.65 13 Al A10 A4 Al 663 3.2 n.d. n.d.

-14 AtlA101 A5 A9 864 5.27 Al A10 A19 A9 863 4.85

+I

16 AI AlO A19 A7 875 4.23 19 Al A10 A19 A25 849 4.8

+I

Al AlOI A19 A22 861 3.49 21 Al AlO A19 A16 889 3.57 22 Al A10 A19 A23 930 5.1 23 Al A10 A19 A26 831 3.56 24 Al AO A19 A27 1899 4.22 A A101 A19 A28 904 3.3 26 Al AO A19 A29 918 3.5 27 A14 Al A2 A9 800 5.01 n.d. 28 A14 Al A3 A9 762 4.81 n.d. 29 A14 Al A12 A9 764 4.92 n.d. A14, Al A4 A9 782 4.9 n.d. 31 A14TAl1 A15 A9 765 5.4 n.d. WO 2004/035062 WO 204105062PCTiAU2003!001377 Example Comp. No. X Y R2 R3 AM Rf SA1SIEC24 8 36 AlO Al A17 A7 919 n.d. I+ n.d.

37 AlO Al A5 A7 898 4.99 38 Al A13 A2 A9 818 5.56 n.d. n.d.

39 Al A13 A5 A7 844 4.72 Al A13 A5 A9 833 _I5.63, n.d. Examle 6 OH R\NH OH HOA 0R R2/ NH R/

NH

Comp. Ri R2 R3 MW Rf SA24 SA48 EC24 42 A20 A20 AS 963 n-d. ni.d. n.d.

43 AS Al A7 690 n.d. n.d. n.d.

44 AS A3 A7 824 n.d. n.d.

-A5 A3 Al 644 3.82 n.d.

46 A5 A21 A7 822 4.73 nmd. 47 AS A21 Al 642 3.39 n.d. n.d.

48 AS A171 A7 898 nd. 49 A5 A4 A7 844 4.9 n.d. ±T 0 5 A A4 Al 664 3.8 n.d. nd WO 2004/035062 WO 204/05062PCT/AU2003/001377 I A4 A9 n.d. n.d.

4. 4 .4 1A44 A7 823 3.98 n.d.

A5 AS j A25 851 5.47 n.d.

56 A5 AS CioH 21 837 5.38 n.d.

57 A5 AS A39 857 4.9 n.d.

58 A5 A5 A40 861 5.01 n.d.

59 A5 A5 A22 AS A5 bis-pentyl 837 4.9 n.d.

61 AS AS A32 851 5.56 n.d.

62 AS A5 A31 837 5.08 n.d.

63 AS AS A30 823 5.1 n.d.

64 A5 AS A33 929 5.82 n.d.

AS A5 A34 942 5.17 n.d.

66 AS AS A41 938 4.81 n.d. n.d.

67 -AS AS A42 952 4.89 n.d. n.d.

68 A5 AS A32 901 5.36 n.d. n.d.

69 AS AS A36 901 5.45 n.d. nd.

AS AS A37 795 4.62 n.d. n.d.

71 AS AS A46 880 4.62 n.d. n.d.

72 AS A5 A47 880 4.81 n.d. n.d.

73 -AS AS A6 893 5.1 n.d. n.d.

74 -AS AS A7 877 4.99 n.d. n.d.

AS AS A23 932 5.63 n.d. n.d.

76 AS AS A8 893 6.09 n.d. n.d.

77 AS AS A9 865 5.63 78 AS A3 A9 813 5.45 n.d. n.d.

79 AS A4 A9 833 5.73 n.d. n.d.

A18 A4 A9 744 1nd. n.d. n.d.

WO 2004/035062 WO 204/05062PCT/A1J20031001377 12 The following compounds were tested against additional organisims with the following results.

1. Micrococcus luteus (ATCC272) 2. Staphylococcus aureus (ATCC292 13) 3. Staphylococcus aureus (ATCC43300) MRSA 4. Enterococcusfaecalis (ATCC292 12) Enterococcusfaecalis (ATCCS 1299) Vancomycin resistant 6. Streptococcus pyro genes (ATCC8668) Compound 1 2 3 4 5 6 76 42 68 69 73 74 +h 66 67 77 51 56 WO 2004/035062 WO 204/05062PCT/A1J20031001377 TABLE 1 Side Arms j N u Al A27 A3

CF

3 0 0

F

3 C "N N' A6 H 0 A6 0 A8 0

-ON

A9 0 0 A32A3 CF3

F

3 C

H'

AIO All A12 Fa 0 NN 3 'N N N

N

A5HA16 H Al cI

H

3 C

N

F

3 C" H A21H 0

H

3 C- /r 0 A4 0 A31 0 A38 0 A vCH.3 A13 vF A14 0 0 H A23 0 NH

F

3 C

N

A19

H

WO 2004/035062 WO 204/05062PCT/A1J20031001377 YA2 6 A27 0 0 A33 H A34 0 0 CI A40 A36 0s A39 0 2

C

A41 0 0 H02 A42 o A43 0 0

NH

HO y l o 0 H0

N

0 H0 0 A46 WO 2004/035062 PCT/AU20031001377 Throughout the specification and the claims unless the context requires otherwise, the term "comprise", or variations such as "comprises" or "comprising", will be understood to apply the inclusion of the stated integer or group of integers but not the exclusion of any other integer or group of integers.

It should be appreciated that various other changes and modifications can be made to any embodiment described without departing from the spirit and scope of the invention.

Claims

1. A method of inhibiting bacterial growth by contacting a bacteria with at least one disaccharide compound of General Formula I, R 1 ,O T W U 0O 0 Z-R 2 R 4 R 3 General Formula I Wherein T is either R or -XR, X is selected from the group consisting of oxygen, sulphur, NHC(O)-, R is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of 1 to 20 carbon atoms, U and Z are independently selected from the group consisting of: OR, NHR, NR(R) wherein R may be the same of different), or S O NH O o AN-J NR N ,R N-NR AN'NR N, R H H H H H H H H NH N R O S Ni-.R "N N-R AO OR .N SR O NR H H H H 0 AN SR 1-N )OR i-N-S-R Ho-S-R O &N 0 0 0 0 0 0 H R R r H HO"'N HOO HO 0 HO HOR^ O R R 1 and R 2 are independently selected from the group consisting of: H, CH 3 CH 2 XR, and C(O)NHR, R 3 and R 4 are independently selected from the group consisting of H, OH, OR, NHCOR, and, W is independently selected from the group consisting of ORL, NHRL, NRLR, or WO 2004/035062 WO 204105062PCTiAU2003!001377 17 S 0 NH 0 a N N RLAN'k R A N N RL /N N RL /N KL H H H H H H H H NH N'R0 0 N) S'R N )IIN' RL 0 k $N 1SRL J,0 'kRL H H H H 0 0) S 0 0 KN SL AN~OL L If L <J H H H6 111 L/ H 0 0 0 0 00 HOA OA HN0' HO-' N~ A~N R HO LI PNN HOKO HO 0o L, LO 6 0o N' R H R RL RL RL H H wherein RL is selected from the group consisting of: a substituted or unsubstituted, linear or branched, saturated or unsaturated C3 to C55 alkyl, heteroalkyl, arylalkyl, alkylaryl. chain.

2. The method of claimi 1, wherein R' is substituted by a moiety selected from the group consisting of: acidic groups, carboxylic acids, sulfonic acids, phosphoric acids, tetrazoles, or other carboxylic acid mimetics, basic groups, amines, guanidiniums, amidines, imidazoles, oxazoles, or other amine mimetics.

3. The method of claim 1, wherein one or more R groups is substituted by a moiety selected from the group consisting of: OH, NO, NO 2 NH 2 N 3 halogen, CF 3 CHF 2 CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylie acid amide, aryl, cycloalkl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, earbamoyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl. WO 2004/035062 PCT/AU2003/001377 18

4. The method of claim 1, wherein the compound comprises R O A W "U 0 Z CH 2 OH HO OH General Formula II Wherein the disaccharide linkage is alpha or beta, A is hydrogen, OR or SR. The method of claim 1, wherein the compound comprises R 1 0 A RL N 1 H 0 Z CH 2 OH HO OH General Formula III Wherein A is hydrogen, OR or SR.

6. The method of claim 1, wherein the bacteria is a Gram bacteria.

7. The method of claim 1, wherein the bacteria is a Gram bacteria.

8. The method of claim 1, wherein the bacteria is selected from the group consisting of an E-coli, Micrococcus luteus, Staphylococcus aureus, Staphylococcus aureus MRSA, Enterococcus faecalis, Enterococcus faecalis Vancomycin resistant and Streptococcus pyogenes. WO 2004/035062 PCT/AU2003/001377 19

9. The method of claim 1, wherein the bacteria is Staphylococcus aureus and the compound is R2 OH NH OH HOO O NH NH 2 R1 wherein R1 is A5 and R2 is A9 and wherein the substituents A are given in TABLE 1 The method of claim 1, wherein the bacteria is Staphylococcus aureus and the compound is R3 OH R3\NHOH HORAN n NH NH R2 O ()n X Y n X Y R2 R3 1 Al A10 All A7 1 Al A10 A4 A9 0 Al A10 A12 A9 0 Al A10 A5 A7 0 Al A10 A5 A9 1 A10 Al A5 A7 and wherein the substituents A are given in TABLE 1

11. The method of claim 1, wherein the bacteria is Staphylococcus aureus and the compound is WO 2004/035062 WO 204105062PCTiAU2003!001377 and wherein the substituents A are given in TABLE 1

12. The method of claim 1, wherein the bacteria is Staphylococcus aureus and the compound is OHR3\NHO HO 0 R2'/N HN=< N NH x y R2 A12 A4 A4 A4 A19 R3 A7 A9 A7 Al A9 A 9 A7 WO 2004/035062 WO 204/05062PCT/A1J20031001377 A19 A19 A19 A22 A16 Al A10 A19 A23 Al A10 A19 A26 Al Al0 A19 A27 Al A10, A19 A28 Al A101 A19 A29 A14 Al A2 A9 Al4 Al A3 A9 A14 At A12 A9 Al4 All A4 A9 AZ4 AlA5 A9 and wherein the substituents A are given in TABLE I

13. The method of claim 1, wherein the bacteria is Staphylococcus aureus and the compound is OH R\NH OH R2' 0 N Y x y Al Al R2 A17 A5 R3 A7 A7 AlA131 A2 A9 Al A13 A5 A7 Al A13 j A5 A9 and wherein the substituents A are given in TABLE 1 WO 2004/035062 WO 204105062PCTiAU2003!001377

14. The method of claim 1, wherein the bacteria is Staphylococcus aureus and the compound is R1 SR2 Al A3 A3 A2 1 A2 1 R3 A8 A7 A7 Al A7 Al A17 A7 A4 A7 A4 Al A44 A7 A5 A2 A5 C 10 11 21 A5 A39 A5 A5 A22 A5 -bis-pentyl A5 A32 A5 A31 A5 A5 A33 A5 A34 A5 A36 A5 A6 A5 A7 A5 A23 A5 A8 A5 A9 A3 A9 A4 A WO 2004/035062 WO 204105062PCTiAU2003!001377 23 A18 A4 L A9 and wherein the substituents; A are given in TABLE 1 The method of claim 1, wherein the bacteria is E. coi and the compound is R2 R A4 A R3 A9 Al .AIOj A4 A7 Al A10 A19 A9 Al AlO A19 A7 Al AlO A19 Al A101 A19 A22 Al A101 A19 A16 Al A101 A19 A23 Al IA10 A19 A26 Al AlO1 A19 A27 Al Al01 A19 A28 Al A10 A19 A29 A14 Al A2 A9 A14 Al A3 A9 A14 Al A12 A9 A14,Al ,A4 ,A9 A141 Al IA15 IA9 and wherein the substituents A are given in TABLE 1 WO 2004/035062 WO 204/05062PCT/A1J20031001377 The method of claim 1, wherein the compound is COMP. R1 R2 R3 42 A20 A20 A8 51 A5 A4 A9 56 A5 A5 CioH 21 A5 A5 A34 67 AS A5 A42 68 A5 A5 A32 69 A5 A5 A36 A5 A5 A37 73 A5 AS A6 74 AS A5 A7 AS A5 A23 76 AS AS A8 77 AS5 AS A9 and wherein the substituents A are given in TABLE 1 and the bacteria is Micrococcus hutits

17. The method of claim 1, wherein the compound is HR3\NHO HO- R2 /H R IN Comp. R1 R2 R3 42 A20 A20 A8 51 AS A4 A9 WO 2004/035062 WO 204/05062PCT/A1J20031001377 56 A5 A-5 CjoH 21 67 A5 AS A42 68 AS A5 A32 69 A5 AS A36 73 A5 AS A6 74 A5 A5 A7 AS A5 A23 76 A-5 AS AS L 77 AS AS A9 and wherein the substituents A are given in TABLE 1 and the bacteria is Staphylococcus aure us.

18. The method of claim 1, wherein the compound is OH R\NH OH /NH NH Comp. Ri R2 R3 42 A20 A20 A8 51 AS A4 A9 56 AS AS CjoH 21 67 AS AS A42 69 AS A5 A36 73 AS5 A-5 A6 74 AS AS A7 AS AS A23 76 A5 A5 A8 77 AS A5 A9 and wherein the substituents A are given in TABLE 1 and wherein the bacteria is Staphylococcus aureus MRSA. WO 2004/035062 WO 204105062PCTiAU2003!001377 26

19. The method of claim 1, wherein the compound is OH R\NH OH HO 0 NH H 2O/N NH Comp. R1 R2 R3 42 A20 A20 A8 51 AS A4 A9 56 AS AS CiolH 21 A5 AS A34 67 AS A5 A42 68 AS A5 A32 69 A5 A5 A36 -A5 A5 A37 73 AS AS A6 74 AS A5 A7 AS AS A23 76 AS AS AS 77 AS AS A9 and wherein the substituents A are given in TABLE 1 and the bacteria is Enterococcusfaecalis. The method of claim 1, wherein the compound is -Comp. R1 R2 R3 42 A20 A20 A8 Si AS A4 A9 56 AS AS CioI4 2 i A5 A5 A34_ WO 2004/035062 WO 204105062PCTiAU2003!001377 67 A5 A5 A42 68 AS A5 A32 69 AS AS A36 A5 A5 A37 73 AS AS A6 74 AS A5 A7 AS A5 A23 76 A5 A5 A8 77 AS AS A9 and wherein the substituents A are given in TABLE 1 and wherein the bacteria is Enterococcusfaecalis Vancomycin resistant

21. The method of claim 1, wherein the compound is OH R3\NH OH HO 00 HO0 H NH R2 /RI COMP. R1 R2 R3 42 A20 A20 A8 51 AS A4 A9 56 AS AS Cl 0 1H 21 AS AS A34 66 AS AS A41 67 AS AS A42 68 AS AS A32 69 A5 AS A36 AS AS A37 73 AS AS A6 74 AS AS A7 AS AS A23 76 AS AS A8 77 AS AS A9 and wherein the substituents A are given in TABLE 1 and the bacteria is Streptococcuspyogenes WO 2004/035062 PCT/AU20031001377 28

22. A method of inhibiting a bacterial infection in a mammal comprising administering an effective amount of a compound of claim 1 to the mammal.

23. An anti-bacterial pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

24. The method of claim 1, wherein the bacterium is a resistant or susceptible strain of a Micrococcus, Streptococcus, Enterococcus or Staphylococcus.