Kinetic and Molecular‐Modelling Study of the Interaction between Staphylococcus aureus PC1 Enzyme and Imipenem

The interactions between imipenem ( 3 ), a clinically significant carbapenem antibiotic, and Staphylococcus aureus PC1 enzyme, were studied in detail. Imipenem behaves as a slow substrate that reacts by a branched pathway, which suggests the formation of a second acyl‐enzyme intermediate. The individual microscopic rate constants for the process were determined. The results were analysed in the light of molecular‐modelling considerations. Based on the analysis, the Ser‐70(O^γ) group in the Michaelis‐Menten complex formed between 3 and PC1 is very distant from the carbonyl group of the β‐lactam ring of 3 , which is consistent with the decreased value of k₂ (Model 2, see Scheme 2) for imipenem relative to an appropriate substrate such as benzylpenicillin ( 2 ). The deacylation is the rate‐determining step of the turnover process. This can be ascribed to the fact that in the deacylation of the second acyl‐enzyme, the H₂O molecule lying closest to the ester group, Wat81, is in an unfavorable orientation to hydrolyse the intermediate.