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 res ponsible for the biosynthesis of alternate cell-wall precursors in bacteria , which are resistant to the glycopeptide antibiotic vancomycin. The crysta l structure has been determined with data extending to 2.5-Angstrom resolut ion. This structure shows that the active site has unexpected interactions and is distinct from previous models for D-alanyl-D-lactate ligase mechanis tic 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 h ydrogen-bonding network, which principally involve His-244. The structure o f D-alanyl-D-lactate ligase provides a revised interpretation of the molecu lar events that lead to vancomycin resistance.