Structure and Dynamics of Burkholderia pseudomallei OXA-57, a Distinctive Low-Efficiency Class D β-Lactamase with Carbapenem-Hydrolyzing Activity
Year: 2026
Type: article
Abstract: The Gram-negative bacterium Burkholderia pseudomallei causes the severe disease melioidosis. β-Lactams, including carbapenems, are the primary treatment for B. pseudomallei infections, but are susceptible to chromosomal serine β-lactamases (SBLs), including the class D enzyme OXA-57. Here we show that recombinant OXA-57 is active toward penicillins and first-generation cephalosporins, slowly hydrolyzes carbapenems, including imipenem and meropenem, but is inactive toward oxyimino-cephalosporins (e.g., ceftazidime). Unlike many OXA enzymes, OXA-57 is sensitive to the mechanism-based SBL inhibitor clavulanic acid, but less so to the diazabicyclooctane avibactam and not to the cyclic boronate vaborbactam. Crystal structures of covalent OXA-57:avibactam and OXA-57:meropenem complexes reveal limited hydrogen-bonding interactions with bound ligands. In molecular dynamics simulations, the bound meropenem acyl-enzyme is mobile, with the 6α-hydroxyethyl group able to sample different orientations, while the water molecule necessary for deacylation is bound only transiently. These observations are consistent with the low level of meropenem turnover, supporting proposals that limited carbapenemase activity is a general property of OXA β-lactamases, and highlight the potential importance of OXA-57 in B. pseudomallei β-lactam resistance.
Source: Biochemistry
Language: English
Subfield: Microbiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: Diamond Light Source, British Council, University of Bristol, Mahidol University, Directorate for Biological Sciences, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, H2020 European Research Council, HORIZON EUROPE European Research Council
Awards: Computational tools for enzyme engineering: bridging the gap between enzymologists and expert simulation, BrisSynBio: Bristol Centre for Synthetic Biology, The UK High-End Computing Consortium for Biomolecular Simulation, G2394358210, Inquire: Software for real-time analysis of binding, Commercialisation of VR for biomolecular design, Predictive multiscale free energy simulations of hybrid transition metal catalysts, Mechanistic diversity, post-translational carbamylation, and inhibitor susceptibility in the OXA beta-lactamase family, The UK High-End Computing Consortium for Biomolecular Simulation, G3835265546, CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface, CCP-BioSim: Biomolecular simulation at the life sciences interface, Predictive computational models for Enzyme Dynamics, Antimicrobial resistance, Catalysis and Thermoadaptation for Evolution and Design, G4884426060, Combined experimental and computational investigations of a nucleophilic displacement reaction with a hydride leaving group, Adaptive Multi-Resolution Massively-Multicore Hybrid Dynamics, Combined quantum mechanics/molecular mechanics (QM/MM) Monte Carlo free energy simulations: a feasibility study, Predicting drug-target binding kinetics through multiscale simulations, BEORHN: Bacterial Enzymatic Oxidation of Reactive Hydroxylamine in Nitrification via Combined Structural Biology and Molecular Simulation, Nicotinic Ligand Development to Target Smoking Cessation and Gain a Molecular Level Understanding of Partial Agonism, BristolBridge: Bridging the Gaps between the Engineering and Physical Sciences and Antimicrobial Resistance, Multiscale Ensemble Computing for Modelling Biological Catalysts, Computational biochemistry: predictive modelling for biology and medicine, The UK High-End Computing Consortium for Biomolecular Simulation
OpenAlex ID: W7223215896