Background: Vancomycin and related glycopeptide antibiotics exert their antimicrobial effect by binding to carboxy-terminal peptide targets in the bacterial cell wall and preventing the biosynthesis of peptidoglycan. Bacteria can resist the action of these agents by replacing the peptide targets with depsipeptides. Rational efforts to design new agents effective against resistant bacteria require a thorough understanding of the structural determinants of peptide recognition by vancomycin.

Results: The crystal structure of vancomycin in complex with N-acetyl-d-alanin has been determined at atomic resolution. Two different oligomeric interactions are seen in the structure: back-to-back dimers, as previously described for the vancomycin-acetate complex, and novel face-to-face dimers, mediated largely by the bound ligands. Models of longer, naturally occurring peptide ligands may be built by extension of N-acetyl-D-alanine. These larger ligands can form an extensive array of polar and nonpolar interactions with two vancomycin monomers in the face-to-face configuration.

Conclusions: A new dimeric form of vancomycin has been found in which two monomers are related in a face-to-face configuration, and bound ligands comprise a large portion of the dimer interface. The relative importance of face-to-face and back-to-back dimers to the antimicrobial activity of vancomycin remains to be established, but face-to-face interactions appear to explain how increased antimicrobial activity may arise in covalent vancomycin dimers.