The natural design of vancomycin family antibiotics to bind their target peptides

The vancomycin family of antibiotics provide a rare opportunity among natural systems to study a molecular recognition process in which both the 'receptor' and the 'ligand' are relatively small molecules. Unlike the vast majority of antibiotics, in the vancomycin family the antibiotic performs the role of the receptor. All members of the family are covalently cross-linked heptapeptides that contain a variety of glycosidic modifications. Their site of action in bacterial cell walls is modelled by simple dipeptides and tripeptides. NMR experiments have been used to characterize the binding of these species through the study of both the complex and the free components. In unbound antibiotics conformational freedom is observed in regions of the molecule not severely restricted by covalent linkages. On binding of the ligand much of this conformational freedom is lost and the hydrophobic side chains of the antibiotics reside close to the intermolecular hydrogen-bonding interactions, thus shielding these interactions from the solvent. The charged amino groups of the N-terminus and disaccharide region of vancomycin are orientated not to optimize intermolecular electrostatic interactions but rather to retain solvation. This causes further hydrophobic faces to be presented to the ligand. Removal of saccharide units from the antibiotics leads to small losses in binding energy but may have considerable influence on the selectivity of the antibiotics. Specific dimerization through the non-ligand-binding faces of ristocetin is observed at millimolar concentrations. The geometry of the dimeric complex enables a close approach of the ligand carboxylate anion and the charged amino group of the novel sugar, ristosamine.