Enzymes of vancomycin resistance: the structure of d -alanine– d -lactate ligase of naturally resistant Leuconostoc mesenteroides

Background: The bacterial cell wall and the enzymes that synthesize it are targets of glycopeptide antibiotics (vancomycins and teicoplanins) and β-lactams (penicillins and cephalosporins). Biosynthesis of cell wall peptidoglycan requires a crosslinking of peptidyl moieties on adjacent glycan strands. The d -alanine– d -alanine transpeptidase, which catalyzes this crosslinking, is the target of β-lactam antibiotics. Glycopeptides, in contrast, do not inhibit an enzyme, but bind directly to d -alanine– d -alanine and prevent subsequent crosslinking by the transpeptidase. Clinical resistance to vancomycin in enterococcal pathogens has been traced to altered ligases producing d -alanine– d -lactate rather than d -alanine– d -alanine.