Antibacterial agents comprising conjugates of glycopeptides and peptidic membrane associating elements

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 —Ra-L- wherein Ra is selected from the group consisting of 4-epi-vancosaminyl, actinosaminyl, and ristosaminyl and L is attached to the amino group of Ra;
• R1 is hydrogen or mannose;
• R2 is selected from the group consisting of —NH2, —NHCH3, —N(CH3)2, —NHL-, and —N(CH3)L-;
• R3 is selected from the group consisting of —CH2CH(CH3)2, [p-OH, m-Cl]phenyl, p-rhamnose-phenyl, [p-rhamnose-galactose]phenyl, [p-galactose-galactose]phenyl, and [p-CH3O-rhamnose]phenyl;
• R4 is selected from the group consisting of —CH2—(CO)NH2, benzyl, [p-OH]phenyl, and [p-OH, m-Cl]phenyl;
• R5 is hydrogen or mannose,
• R6 is selected from the group consisting of hydrogen, 4-epi-vancosaminyl, vancosaminyl, actinosaminyl, ristosaminyl, or acosaminyl;
• or R6 is a group of the formula Rb-L- wherein Rb is selected from the group consisting of 4-epi-vancosaminyl, vancosaminyl, actinosaminyl, ristosaminyl and acosaminyl and L is attached to the amino group of Rb;
• or R6 is a group Rb—R7 wherein Rb is selected from the group consisting of 4-epi-vancosaminyl, vancosaminyl, actinosaminyl, ristosaminyl and acosaminyl and R7 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-.