Multiscale Simulations Identify Origins of Differential Carbapenem Hydrolysis by the OXA-48 β-Lactamase.

ABSTRACT: OXA-48 β-lactamases are frequently encountered in bacterial infections caused by carbapenem-resistant Gram-negative bacteria. Due to the importance of carbapenems in the treatment of healthcare-associated infections and the increasingly wide dissemination of OXA-48-like enzymes on plasmids, these β-lactamases are of high clinical significance. Notably, OXA-48 hydrolyzes imipenem more efficiently than other commonly used carbapenems, such as meropenem. Here, we use extensive multiscale simulations of imipenem and meropenem hydrolysis by OXA-48 to dissect the dynamics and to explore differences in the reactivity of the possible conformational substates of the respective acylenzymes. Quantum mechanics/molecular mechanics (QM/MM) simulations of the deacylation reaction for both substrates demo

SUBMITTER: Hirvonen VHA 

PROVIDER: S-EPMC9097296 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature