Molecular mechanisms of antibiotic resistance: QM/MM modelling of deacylation in a class A beta-lactamase.

Modelling of the first step of the deacylation reaction of benzylpenicillin in the E. coli TEM1 beta-lactamase (with B3LYP/6-31G + (d)//AM1-CHARMM22 quantum mechanics/molecular mechanics methods) shows that a mechanism in which Glu166 acts as the base to deprotonate a conserved water molecule is both energetically and structurally consistent with experimental data; the results may assist the design of new antibiotics and beta-lactamase inhibitors.