Interaction of tazobactam with Staphylococcus aureus PC1 beta-lactamase: a molecular modelling and enzyme kinetics study.

Tazobactam is a highly potent inhibitor of beta-lactamases. A kinetic study of its interaction with the class A Staphylococcus aureus PC1 beta-lactamase was undertaken which showed competitive inhibition with the substrate nitrocefin. When the enzyme was preincubated with inhibitor for varying lengths of time, the kinetic profile was consistent with a portion of the enzyme being irreversibly inactivated. Using the crystal structure of the enzyme a molecular modelling study revealed the likely interactions of the inhibitor at the active site of the enzyme. It was shown that a possible reaction could occur in which Ser-70 was crosslinked via a fragment of tazobactam to Lys-73. Trypsin digest experiments supported the proposed crosslinking reaction.