The molecular basis of vancomycin resistance in clinically relevant Enterococci:: Crystal structure of D-alanyl-D-lactate ligase (VanA)

D-alanine-D-lactate ligase from Enterococcus faecium BM4147 is directly responsible for the biosynthesis of alternate cell-wall precursors in bacteria, which are resistant to the glycopeptide antibiotic vancomycin. The crystal structure has been determined with data extending to 2.5-Angstrom resolution. This structure shows that the active site has unexpected interactions and is distinct from previous models for D-alanyl-D-lactate ligase mechanistic studies. It appears that the preference of the enzyme for lactate as a ligand over D-alanine could be mediated by electrostatic effects and/or a hydrogen-bonding network, which principally involve His-244. The structure of D-alanyl-D-lactate ligase provides a revised interpretation of the molecular events that lead to vancomycin resistance.