Molecular basis of the activity of antibiotics of the vancomycin group

Abstract

The formation of a carboxylate anion binding pocket in the antibiotics of the vancomycin group is made energetically more favorable by the S stereochemistry of residue 3 relative to the R stereochemistries of residues 1, 2, and 4. Pocket formation is further favoured by the covalent cross-linking of the sidechains of residues 2 and 4, and in some cases, also of residues 1 and 3. In the absence of the latter cross-link in vancomycin itself, the pocket is only partially formed in the free antibiotic, and is in equilibrium with a second conformation in which the peptide backbone alternates as in a β-pleated sheet. The sugar vancosamine plays a role in the thermodynamics of binding of vancomycin to cell wall analogues. This role is based upon a hydrophobic interaction between the 6-methyl group of the sugar and the methyl group of the C-terminal alanine of the cell-wall analogue. The hydrophobic interaction is however only significant in the presence of the nearby charged amino group of the sugar. It is believed that the charged group, by local ordering of the water structure, strengthens the hydrophobic interaction. The sugar mannose in ristocetin A is able, by partially shielding the non-C-terminal alanine methyl group of the dipeptide cell wall analogue from water, to increase the binding of ristocetin A to this analogue. However, in the binding of the tripeptide cell-wall analogue, this same methyl group is shielded from water by the sidechain of lysine, and mannose loses a significant role in the thermodynamics of binding. This observation accounts for the much larger increase in binding, on passing from di- to tri-peptide, observed for vancomycin (which lacks mannose) relative to ristocetin A (which possesses mannose). © 1989 IUPAC