Structures of glycopeptide antibiotics with peptides that model bacterial cell-wall precursors.

The vancomycin-related antibiotics balhimycin and degluco-balhimycin have been crystallized in complexes with di-, tri- and pentapeptides that emulate bacterial cell-wall precursors, and four structures determined at atomic resolution (<1 A). In addition to the features expected from previous structural and spectroscopic studies, two new motifs were observed that may prove important in the design of antibiotics modified to overcome bacterial resistance. A changed binding mode was found in two dipeptide complexes, and a new type of face-to-face oligomerization (in addition to the well-established back-to-back dimerization) was seen when the model peptide reaches a critical fraction of the size of the cell-wall precursor pentapeptide. The extensive interactions involving both antibiotic and peptide molecules in this interface should appreciably enhance the kinetic and thermodynamic stability of the complexes. In the pentapeptide complex, the relative positions of the peptides are close to those required for d-Ala elimination, so this structure may provide a realistic model for the prevention of the enzyme-catalyzed cell-wall crosslinking by antibiotic binding.