Antibacterial agents comprising conjugates of glycopeptides and peptidic membrane associating elements

1. An antibacterial compound of formula V-L-W-X; wherein:

V is a glycopeptide moiety which inhibits peptidoglycan biosynthesis in bacteria;

L is a linking group;

W is a peptidic membrane-associating element and is either a membrane binding peptide including at least one sequence (Xaa) n , where n is from 1 to 12 and each Xaa is independently lysine or arginine, and having an overall positive charge; or a membrane-inserting peptide;

X is a membrane-insertive element and is a lipophilic chain wherein the lipophilic chain is described as:

having from 6 to 30 carbon atoms including those of any aromatic rings;

straight or branched containing one to three branch points;

saturated or unsaturated containing one to four double or triple bonds;

optionally having 1, 2 or 3 heteroatoms (in addition to those in any aromatic rings) independently selected from the group consisting of S, O and N;

optionally containing one or more aromatic rings, which may be fused and each of which may contain from 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S; and

optionally having from one to three substituents selected from the group consisting of hydroxy, -SH, amino and halo; and

V-L- is of the formula:

wherein:

Y and Y′ are independently hydrogen or chloro;

R is selected from the group consisting of hydrogen, 4-epi-vancosaminyl, actinosaminyl, and ristosaminyl, or R is a group of the formula —R a -L- wherein R a is selected from the group consisting of 4-epi-vancosaminyl, actinosaminyl, and ristosaminyl and L is attached to the amino group of R a ;

R 1 is hydrogen or mannose;

R 2 is selected from the group consisting of —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHL-, and —N(CH 3 )L-;

R 3 is selected from the group consisting of —CH 2 CH(CH 3 ) 2 , [p-OH, m-Cl]phenyl, p-rhamnose-phenyl, [p-rhamnose-galactose]phenyl, [p-galactose-galactose]phenyl, and [p-CH 3 O-rhamnose]phenyl;

R 4 is selected from the group consisting of —CH 2 —(CO)NH 2 , benzyl, [p-OH]phenyl, and [p-OH, m-Cl]phenyl;

R 5 is hydrogen or mannose,

R 6 is selected from the group consisting of hydrogen, 4-epi-vancosaminyl, vancosaminyl, actinosaminyl, ristosaminyl, or acosaminyl; or R 6 is a group of the formula R b -L- wherein R b is selected from the group consisting of 4-epi-vancosaminyl, vancosaminyl, actinosaminyl, ristosaminyl and acosaminyl and L is attached to the amino group of R b ; or R 6 is a group R b —R 7 wherein R b is selected from the group consisting of 4-epi-vancosaminyl, vancosaminyl, actinosaminyl, ristosaminyl and acosaminyl and R 7 is an organic side chain moiety which is no more than 1000 Da; and

Ter1 is hydroxy or -L-, provided that the compound includes at least one group -L-.

2. A compound according to claim 1 wherein R 6 is a group R b —R 7 wherein

R b is selected from the group consisting of 4-epi-vancosaminyl, vancosaminyl, actinos-aminyl, ristosaminyl and acosaminyl and

R 7 includes those of the formula —CH 2 —R 8 , in which R 8 is selected from the group consisting of hydrogen, C 1 –C 15 alkyl, C 2 –C 15 alkenyl, C 2 –C 15 alkynyl, C 1 –C 7 haloalkyl, acenaphthenyl, 2-fluorenyl, 9,10-dihydro-2-phenanthrenyl, R 9 , C 1 –C 11 alkyl-R 9 , C 2 –C 7 alkenyl-R 9 , C 2 –C 7 alkynyl-R 9 , and C 1 –C 7 alkyl-O—R 9 wherein R 9 is a radical of the formula:

—R 10 -[linker ( 0 or 1)—R 10 ] ( 0 or 1)

wherein each R 10 is independently selected from the group consisting of phenyl, C 5 –C 6 cycloalkyl, naphthyl, and thienyl, each of which is unsubstituted or is optionally substituted with one or two substituents independently selected from the group consisting of C 1 –C 10 alkyl, C 1 –C 2 haloalkyl, C 1 –C 2 haloalkoxy, C 1 –C 10 alkoxy, halo, cyano, and nitro;

and “linker” is selected from the group consisting of C 1 –C 3 -alkylene, —O—C 1 –C 6 alkylene, C 1 –C 6 -alkylene-O—, —O—, —N(H or C 1 –C 3 lower alkyl)-, —S—, —SO—, —S 2 —, —NH—C(O)—, —C(O)—NH—, —CH═CH—, —C≡C—, —N═N—, —O—C(O)—, and —C(O)—O—.

3. A compound according to any one of the preceding claims wherein V is selected from the group consisting of vancomycin, chloroeremomycin, teicoplanin, A 2 -2, ristocetin A, eremomycin, balkimycin, actinodin A, complestanin, chloropeptin 1, kistamycin A, and avoparcin.

4. A compound according to any one of the preceding claims wherein W is a membrane-binding peptide comprising from 2 to 10 contiguous residues selected from lysine and arginine.

5. A compound according to claim 4 wherein the membrane-binding peptide comprises from 7 to 30 amino acids.

6. A compound according to claim 4 wherein the membrane-binding peptide is selected from the group consisting of:

DGPKKKKKKSPSKSSG (SEQ ID NO: 4);

GSSKSPSKKKKKKPGD (SEQ ID NO: 5);

SPSNETPKKKKKKRFSFKKSG (SEQ ID NO: 6);

DGPKKKKKKSPSKSSK (SEQ ID NO: 7); and

SKDGKKKKKKSKTK (SEQ ID NO: 8).

7. A compound according to claim 1 wherein W is a membrane-inserting peptide selected from the group consisting of α-defensins, β-defensins, and bacteriocins.

8. A compound according to claim 7 wherein said β-defensin is a tachyplesin.

9. A compound according to claim 1 wherein said membrane-inserting peptide is a magainin.

10. A compound according to claim 1 wherein said membrane-inserting peptide is maculatin 1.1 or caerin 1.1.

11. A method of treating a bacterial infection in a subject which method comprises administering to said subject an effective amount of the antibacterial agent of claim 1 .

12. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.