Crystal Structures of the Complexes between Vancomycin and Cell-Wall Precursor Analogs

The crystal structures of three vancomycin complexes with two vancomycin-sensitive cell-wall precursor analogs (diacetyl-Lys-d-Ala-d-Ala and acetyl-d-Ala-d-Ala) and a vancomycin-resistant cell-wall precursor analog (diacetyl-Lys-d-Ala-d-lactate) were determined at atomic resolutions of 1.80 Å, 1.07 Å, and 0.93 Å, respectively. These structures not only reconfirm the “back-to-back” dimerization of vancomycin monomers and the ligand-binding scheme proposed by previous experiments but also show important structural features of strategies for the generation of new glycopeptide antibiotics. These structural features involve a water-mediated antibiotic–ligand interaction and supramolecular structures such as “side-by-side” arranged dimer-to-dimer structures, in addition to ligand-mediated and “face-to-face” arranged dimer-to-dimer structures. In the diacetyl-Lys-d-Ala-d-lactate complex, the interatomic O⋯O distance between the carbonyl oxygen of the fourth residue of the antibiotic backbone and the ester oxygen of the d-lactate moiety of the ligand is clearly longer than the corresponding N–H⋯O hydrogen-bonding distance observed in the two other complexes due to electrostatic repulsion. In addition, two neighboring hydrogen bonds are concomitantly lengthened. These observations provide, at least in part, a molecular basis for the reduced antibacterial activity of vancomycin toward vancomycin-resistant bacteria with cell-wall precursors terminating in –d-Ala-d-lactate.