Mechanism of Action of OXA‐58 β‐Lactamase

Abstract

Carbapenems such as imipenem and meropenem are β‐lactam antibiotics with a wide spectrum of activity, initially designed to overcome β‐lactam resistance due to their stability toward most β‐lactamases. However, as a result of selective pressure these carbapenems have succumbed to the hydrolytic power of β‐lactamases. These enzymes hydrolyze the β‐lactam bond of these antibiotics. They are classified in four classes based on their primary sequences, classes A, B, C and D. Classes A, C and D are serine‐active site β‐lactamases and class B β‐lactamases are metallo‐enzymes. The progressively increasing ability of all four classes of β‐lactamases to hydrolyze carbapenems has been documented. Among them, Carbapenem‐hydrolyzing Class D β‐lactamases (CHDLs) are directly associated with outbreaks of carbapenem‐resistant Acinetobacter baumannii around the world and have emerged as a major problem in treatment of multidrug resistant A. baumannii, for which carbapenems have been the drug of choice. We have undertaken a structural study using H/D exchange and a kinetic study using a number of OXA‐58 mutants to delineate the mechanism of hydrolysis of imipenem by OXA‐58. Our studies show that OXA‐58 employs enzyme dynamics to gain specificity toward imipenem hydrolysis.