title: Insight into the Mechanism of Hydrolysis of Meropenem by OXA-23 Serine-β-lactamase Gained by Quantum Mechanics/Molecular Mechanics Calculations.
abstract: 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 OXA-23, a class D β-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 experimental kinetic measurements, validating the expected reaction path.
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, CNR , Via Mario Bianco 9, 20131 Milan, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Sgrignani
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano , Via L. Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grazioso
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano , Via L. Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: De Amici
mesh_terms: D018360:Crystallography, X-Ray; D006868:Hydrolysis; D000077731:Meropenem; D011789:Quantum Theory; D013845:Thienamycins / Q000737:chemistry*; D001618:beta-Lactamases / Q000737:chemistry*
chemical_list: D013845:Thienamycins; C466679:beta-lactamase OXA-23; D001618:beta-Lactamases; D000077731:Meropenem