AU2003266863A1 - Carbohydrate based anti-bacterials - Google Patents

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. 5 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 10 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. 15 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 20 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 25 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 30 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 [WO0064915 and W09926596]. A further class of disaccharide molecules, based on a sub-structure of vancomycin was shown to have antibacterial activity against vancomycin resistant 5 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 10 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. 15 The present invention may also be directed to a method of screening such compounds for anti-bacterial activity by contacting the compounds with a Gram positive 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 20 contacting a bacteria with at least one disaccharide compound of General Formula I, o T W U 0 0 Z R2

R

4

R

3 General Formula I 25 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 PCT/AU2003/001377 3 heteroalkyl, aryl, heteroaryl, arylalkyl 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 5 amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted, 10 U and Z independently selected from OR, NHR, NR(R) (where R may be the same or different), or the following non-limiting set, S 0 NH 0 O N 'RKN 'R N N N'R N N'R /N R H H H H H H H H NH N' O S N kS'R AN ilN'R O, kO'R IN ',SR H H H H 0 N SR I-N OR HN-S-R /O-R 0 H H H O O H H 0 0 0 0I 00 H N HO' 'O HO 0 HO H N RH R R R' "H 15 R1 and R2 are independently selected from H, CH 3 , CH 2 XR, and C(O)NHR,

R

3 and R 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 0 NH 0 O N AN'R N O'RL !NN N'R N N' RL N RL H H H H H H H H NH N'R O S f~K L L S<N~ R N S'RL N N'RL O O'RL - N SRL H H H H O 0 S 0 0 N SRL /N ORL N RL O- RL O H H H O R 0 0 HO HO' O HO'O HO' HO N RL H RL RLO RLO RL,- H Wherein RL is a substituted or unsubstituted, linear or branched, saturated or unsaturated C3 to C55 alkyl, heteroalkyl, arylalkyl, alkylaryl chain. Substituents may 5 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 10 bacterial growth by contacting a bacteria with at least one disaccharide compound of General Formula II,

R

4 0 A W "'U 0 Z CH 2 OH HO OH 15 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 5 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, 5

R

4 0 A 0 RL N U H 0 Z CH 2 OH HO OH General Formula III 10 Wherein A is defined as in General Formula I, and U, Z, RL 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 15 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 20 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. 25 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. 5 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 10 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 15 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 20 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 25 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 30 degrees C.

WO 2004/035062 PCT/AU2003/001377 7 Example 1 R2 OH NH OH HO 0 H OO NH

NH

2 R1 Comp. No. R I R2 Mass R, 1SA241SA481EC24 1 A5 A9 679 4.62 + n.d. 5 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 10 SA48 S.aureus after 48 hours exposure EC24 E. coli after 24 hours exposure Example 2 R3\ OHR3 NH OH HO O HO NH NH R2 O ()n X y Comp. No. n X Y R2 R3 MS R, SA24 SA48 EC24 2 1 Al A10 All A7 875 n.d + + 3 1 A1 A10 A4 A9 831 n.d + + . 4 0 Al A10 A12 A9 800 5.1 + n.d 5 0 Al AlO A5 A7 862 4.92 + + . 6 0 Al A10 A5 A9 851 5.36 + n.d n.d. 7 1 A10Al A5 A7 876 5.01 + + 15 WO 2004/035062 PCT/AU2003/001377 8 Example 3 R3\ OH NH OH HO R2/ O=NH 0 Comp. No. R2 R3 MW Rf SA24 SA48 EC24 8 A5 A7 824 4.72 + + 9 A5 A9 813 5.56 + n.d. n.d.

WO 2004/035062 PCT/AU2003/001377 9 Example 4 H R3\ NH OH HO 0 R2 HN=N NH x Y Comp. No. X Y R2 R3 MW Rf SA2 SA48 EC2 10 Al A10 A12 A7 875 n.d. + + 11 Al A10 A4 A9 831 5.18 + + + 12 Al A10 A4 A7 843 4.65 + + + 13 Al A10 A4 Al 663 3.2 + n.d. n.d. 14 Al A10 A5 A9 864 5.27 + + 15 Al A10 A19 A9 863 4.85 + + + 16 Al A10 A19 A7 875 4.23 + + + 19 Al A10 A19 A25 849 4.8 + + + 20 Al A10 A19 A22 861 3.49 + + + 21 Al A10 A19 A16 889 3.57 + + + 22 Al A10 A19 A23 930 5.1 + + + 23 Al A10 A19 A26 831 3.56 + + + 24 Al A10 A19 A27 899 4.22 + + + 25 Al A10 A19 A28 904 3.3 + + + 26 Al A10 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. + 30 A14 Al A4 A9 782 4.9 + n.d. + 31 A14 Al A15 A9 765 5.4 + n.d. + 5 WO 2004/035062 PCT/AU2003/001377 10 Example 5 R3\ OH NH OH HO O NH NH R2/ s y x Comp. No. X Y R2 R3 MW Rf S S EC24 36 A10 Al A17 A7 919 n.d. + + n.d. 37 A10 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 + + 40 Al A13 A5 A9 833 5.63 + n.d. 5 Example 6 R3\ OH NH OH HO O O HO O R2 NH R/ NH Comp. R1 R2 R3 MW Rf SA24 SA48 EC24 42 A20 A20 A8 963 n.d. + n.d. n.d. 43 A5 Al A7 690 n.d. + n.d. n.d. 44 A5 A3 A7 824 n.d. + + n.d. 45 A5 A3 Al 644 3.82 + n.d. 46 A5 A21 A7 822 4.73 n.d. + 47 A5 A21 Al 642 3.39 + n.d. n.d. 48 A5 A17 A7 898 n d. + + 49 A5 A4 A7 844 4.9 n.d. + . 50 A5 A4 Al 664 3.8 + n.d. n.d.

WO 2004/035062 PCT/AU2003/001377 11 51 A5 A4 A9 n.d. n.d. n.d. n.d. 52 A5 A44 A7 823 3.98 n.d. + 55 A5 A5 A25 851 5.47 + + n.d. 56 A5 A5 C 10

H

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 AS A22 n.d. + + 60 A5 A5 bis-pentyl 837 4.9 + + n.d. 61 A5 AS A32 851 5.56 + + n.d. 62 A5 AS A31 837 5.08 + + n.d. 63 A5 A5 A30 823 5.1 + + n.d. 64 A5 AS A33 929 5.82 + + n.d. 65 A5 A5 A34 942 5.17 + + n.d. 66 AS A5 A41 938 4.81 - n.d. n.d. 67 A5 A5 A42 952 4.89 - n.d. n.d. 68 AS A5 A32 901 5.36 - n.d. n.d. 69 A5 AS A36 901 5.45 + n.d. n.d. 70 A5 AS A37 795 4.62 - n.d. n.d. 71 A5 AS A46 880 4.62 - n.d. n.d. 72 A5 A5 A47 880 4.81 - n.d. n.d. 73 A5 A5 A6 893 5.1 + n.d. n.d. 74 A5 A5 A7 877 4.99 + n.d. n.d. 75 A5 A5 A23 932 5.63 + n.d. n.d. 76 A5 A5 A8 893 6.09 + n.d. n.d. 77 A5 A5 A9 865 5.63 + + 78 A5 A3 A9 813 5.45 + n.d. n.d. 79 A5 A4 A9 833 5.73 + n.d. n.d. 80 A18 A4 A9 744 n.d. + n.d. n.d.

WO 2004/035062 PCT/AU2003/001377 12 The following compounds were tested against additional organisims with the following results. 1. Micrococcus luteus (ATCC272) 2. Staphylococcus aureus (ATCC29213) 5 3. Staphylococcus aureus (ATCC43300) MRSA 4. Enterococcusfaecalis (ATCC29212) 5. Enterococcusfaecalis (ATCC51299) Vancomycin resistant 6. Streptococcus pyrogenes (ATCC8668) Compound 1 2 3 4 5 6 76 + + + + + + 42 + + + + + + 75 + + + + + + 68 + + - + - + 65 + - - + - + 69 + + + + - + 70 + - - + - + 73 + + + + + + 74 + + + + + + 66 - - - - - + 67 + + + + + + 77 + + + + + + 51 + + + + + + 56 + + + + + + 10 WO 2004/035062 PCT/AU2003/001377 13 TABLE 1 Side Arms 0 0 0 H H3C \/ 0 Al A2 A3 A4

CF

3 00 0 N

F

3 C N O A5 H0 A6 IA 0 0 A8 A31 0 0 A9 A38 o 0 0 A32 A37 A30

CF

3 F3C N CH 3 F 3 F 3 C H A10 All A12 A13 A14 0 '~ -~ NH F 3 C 00 F N N N /F3C N A15 H A16 H A17 A18 H F. H 3 C N

F

3 0 ")a N)' A20 H A21 H / A22 0 0 0 NH A25 H A23

F

3 C N A19 H WO 2004/035062 PCT/AU2003/001377 14 YA2 6 A27 0 N / A33 H A34 0 0 "N ~ 0 - A40 A36 o/ A39 0 0

HO

2 C HO2C NH NH A41 0 A42 o 0 H020 NH0 A 43 0H 0 A44 H NH H 0 HON A45o 0 0 A46 H 0 A47 o WO 2004/035062 PCT/AU2003/001377 15 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. 5 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 (15)

1. A method of inhibiting bacterial growth by contacting a bacteria with at least one disaccharide compound of General Formula I, W U 0 0 Z R2 R 4 R 3 5 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, 10 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 0 NH 0 O N N'R /N 'R /N )N.R N)N'R /N R H H H H H H H H NH N'R O s o N S'R N N'R A 0 0 R N SR 0 N'R H H H H H 0 0 S 0 o S /NK SR ' -N )OR N-S"-R -O-S-R O H H H O RH 0 0 0 0 0 0I 0

11. " H 0 HO NA HO' O>' HO OA HO''/ HO A R RH R R 1 R H 0r RH R1 and R 2 are independently selected from the group consisting of: H, CH 3 , CH 2 XR, 15 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 PCT/AU2003/001377 17 S 0 NH 0 O N N'RL N 'RL N N'RL N N'RL N RL H H H H H H H H NH N' R S O N S'RL N RL O O'R N SRL O RL H H H H a s 0 SS0 Nk S OR N RL N RL- L O-' N H H H 1 1 RL/ H 0 0 0 0 0 0 00 HoLIN HOO HQ'POA HO' \Y HO 0 N R H R RL-o 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. 5 2. The method of claim 1, wherein RL 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. 10 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, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, 15 aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, carbamoyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl. WO 2004/035062 PCT/AU2003/001377 18 4. The method of claim 1, wherein the compound comprises R 1 0 A W U 0 Z CH 2 OH HO OH 5 General Formula II Wherein the disaccharide linkage is alpha or beta, A is hydrogen, OR or SR. 5. The method of claim 1, wherein the compound comprises 10 R1 0 A 0 RL<N U H 0 Z CH 2 OH HO OH General Formula III Wherein A is hydrogen, OR or SR. 15 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. 20 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 HO- 00 HO O NH NH 2 R1 wherein R1 is A5 and R2 is A9 5 and wherein the substituents A are given in TABLE 1 10. The method of claim 1, wherein the bacteria is Staphylococcus aureus and the compound is R3\ OH NH OH HO O HO /NH NH R2 O ()n x Y 10 n X Y R2 R3 1 Al A10 All A7 1 Al A10 A4 A9 0 Al A10 A12 A9 0 A1 A10 A5 A7 0 A1 A10 A5 A9 1 AlO A1 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 15 WO 2004/035062 PCT/AU2003/001377 20 R3\ OH NH OH HO 0 HO H04 R2 O 0 A5 A7 A5 A9 and wherein the substituents A are given in TABLE 1 5

12. The method of claim 1, wherein the bacteria is Staphylococcus aureus and the compound is R3\ OH R\NH OH HOA0R R2/ HN N NH x Y 10 X Y R2 R3 Al A1O A12 A7 Al Al1 A4 A9 Al A10 A4 A7 Al A10 A4 Al Al AlO A5 A9 Al A10 A19 A9 Al A1O A19 A7 WO 2004/035062 PCT/AU2003/001377 21 Al A10 A19 A25 Al A10 A19 A22 Al A10 A19 A16 Al A10 A19 A23 Al A10 A19 A26 Al A1O A19 A27 Al A10 A19 A28 Al A10 A19 A29 A14 Al A2 A9 A14 Al A3 A9 A14 Al A12 A9 A14 Al A4 A9 A14 Al A15 A9 and wherein the substituents A are given in TABLE 1

13. The method of claim 1, wherein the bacteria is Staphylococcus aureus and the 5 compound is R3\ OH NHOH HO A 0 iO0 /NH / NH R2 Y X X Y R2 R3 AlO Al A17 A7 A10 Al A5 A7 Al A13 A2 A9 Al A13 A5 A7 Al A13 A5 A9 and wherein the substituents A are given in TABLE 1 10 WO 2004/035062 PCT/AU2003/001377 22

14. The method of claim 1, wherein the bacteria is Staphylococcus aureus and the compound is OH R\NH OH HO 45 HOA /NH N H R2 R 5 Ri R2 R3 A20 A20 A8 A5 Al A7 A5 A3 A7 A5 A3 Al A5 A21 A7 A5 A21 Al A5 A17 A7 A5 A4 A7 A5 A4 Al A5 A44 A7 A5 A5 A25 A5 A5 C 10 H 21 A5 A5 A39 A5 A5 A40 A5 A5 A22 A_ A5 bis-pentyl A5 A5 A32 A5 A5 A31 A5 A5 A30 A5 A5 A33 A5 A5 A34 A5 A5 A36 AS AS A6 A5 AS A7 A5 A5 A23 AS A5 A8 AS A5 A9 AS A3 A9 AS A4 A9 WO 2004/035062 PCT/AU2003/001377 23 A18 I A4 A9 and wherein the substituents A are given in TABLE 1

15. The method of claim 1, wherein the bacteria is E. coli and the compound is R3\ OH NH OH HO O O HO A O R 2 /NH NH NH 5 X Y X Y R2 R3 Al A10 A4 A9 Al A1O A4 A7 Al A10 A19 A9 Al AlO A19 A7 Al A10 A19 A25 Al A10 A19 A22 Al A10 A19 Al6 Al AlO A19 A23 Al AlO A19 A26 Al AlO A19 A27 Al AlO A19 A28 Al A10 A19 A29 A14 Al A2 A9 A14 Al A3 A9 A14 Al A12 A9 A14 Al A4 A9 A14 Al A15 A9 and wherein the substituents A are given in TABLE 1 WO 2004/035062 PCT/AU2003/001377 24

16. The method of claim 1, wherein the compound is R3\ OH NH OH H O O OL NH H R2 RI Comp. RI R2 R3 42 A20 A20 A8 51 A5 A4 A9 56 A5 A5 CioH 21 65 A5 A5 A34 67 A5 A5 A42 68 A5 A5 A32 69 A5 A5 A36 70 A5 A5 A37 73 A5 A5 A6 74 A5 A5 A7 75 A5 A5 A23 76 A5 A5 A8 77 A5 A5 A9 5 and wherein the substituents A are given in TABLE 1 and the bacteria is Micrococcus luteus .

17. The method of claim 1, wherein the compound is H R3\NH OH HO 10 R 2 /NH R NH Comp. RI R2 R3 42 A20 A20 A8 51 A5 A4 A9 WO 2004/035062 PCT/AU2003/001377 25 56 A5 A5 CioH 21 67 A5 A5 A42 68 A5 A5 A32 69 A5 A5 A36 73 A5 A5 A6 74 A5 A5 A7 75 A5 A5 A23 76 A5 A5 A8 77 A5 A5 A9 and wherein the substituents A are given in TABLE 1 and the bacteria is Staphylococcus aureus.

18. The method of claim 1, wherein the compound is 5 R3\ OH NHOH HO-4I /NH /NH R2 RI Comp. R1 R2 R3 42 A20 A20 A8 51 A5 A4 A9 56 A5 A5 C 1 0 H 21 67 A5 A5 A42 69 A5 A5 A36 73 A5 A5 A6 74 A5 A5 A7 75 A5 A5 A23 76 A5 A5 A8 77 A5 A5 A9 and wherein the substituents A are given in TABLE 1 and wherein the bacteria is Staphylococcus aureus MRSA. 10 WO 2004/035062 PCT/AU2003/001377 26

19. The method of claim 1, wherein the compound is OH R3\NH OH HO O HO/H 2 N HR N H R2 RI Comp. R1 R2 R3 42 A20 A20 A8 51 A5 A4 A9 56 A5 A5 C 10 H 21 65 A5 A5 A34 67 A5 A5 A42 68 A5 A5 A32 69 A5 A5 A36 70 A5 A5 A37 73 A5 A5 A6 74 A5 A5 A7 75 A5 AS A23 76 A5 A5 A8 77 A5 A5 A9 5 and wherein the substituents A are given in TABLE 1 and the bacteria is Enterococcusfaecalis.

20. The method of claim 1, wherein the compound is R3\ OH NH OH HO HO O 10 R2R Comp. Ri R2 R3 42 A20 A20 A8 51 A5 A4 A9 56 A5 A5 C 10 H 21 65 A5 A5 A34 WO 2004/035062 PCT/AU2003/001377 27 67 A5 A5 A42 68 A5 A5 A32 69 A5 A5 A36 70 A5 A5 A37 73 A5 A5 A6 74 A5 A5 A7 75 A5 A5 A23 76 A5 A5 A8 77 A5 A5 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 5 OH R3\NH OH HO O HO H NH R2 ~ R1 Comp. R1 R2 R3 42 A20 A20 A8 51 A5 A4 A9 56 A5 A5 C 10 H 21 65 A5 A5 A34 66 A5 A5 A41 67 A5 A5 A42 68 A5 A5 A32 69 A5 A5 A36 70 A5 A5 A37 73 A5 A5 A6 74 A5 A5 A7 75 A5 A5 A23 76 A5 A5 A8 77 A5 A5 A9 and wherein the substituents A are given in TABLE 1 and the bacteria is Streptococcuspyogenes 10 WO 2004/035062 PCT/AU2003/001377 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 5 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. 10