Insight into the Mechanism of Hydrolysis of Meropenem by OXA-23 Serine-β-lactamase Gained by Quantum Mechanics/Molecular Mechanics Calculations

The fast and constant development of drug resistant bacteria represents a serious medical emergency. To, overcome this problem, the development of drugs with new structures and modes of action is urgently needed. In this work, we investigated, at the atomistic level, the mechanisms of hydrolysis of Meropenem by QXA-723, a class D beta-lactamase combining unbiased classical molecular dynamics and umbrella sampling simulations with classical force field-based-and quantum mechanics/molecular mechanics potentials. Our calculations provide a detailed structural and dynamic picture. of the molecular steps-leading to the formation of the Meropenem-OXA-23 covalent adduct, the-subsequent hydrolysis, and the final release of the inactive antibiotic. In this mechanistic framework, the predicted activation energy is in good agreement with experiniental kinetic measurements, validating the expected reaction path.