Antimicrobial resistance conferred by OXA-48 β-lactamases: towards a detailed mechanistic understanding

Viivi H A Hirvonen*, James Spencer*, Marc W Van Der Kamp*

*Corresponding author for this work

Research output: Contribution to journalBook/Film/Article review (Academic Journal)peer-review

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Abstract

OXA-48-type β-lactamases are now routinely encountered in bacterial infections caused by carbapenem-resistant Enterobacterales. These enzymes are of high and growing clinical significance due to the importance of carbapenems in treatment of healthcare-associated infections by Gram-negative bacteria, the wide and increasing dissemination of OXA-48 enzymes on plasmids, and the challenges posed by their detection. OXA-48 confers resistance to penicillin (which is efficiently hydrolyzed) and carbapenem antibiotics (more slowly broken down). In addition to the parent enzyme, a growing array of variants of OXA-48 is now emerging. The spectrum of activity of these variants varies, with some hydrolyzing expanded-spectrum oxyimino-cephalosporins. The growth in importance and diversity of the OXA-48 group has motivated increasing numbers of studies that aim to elucidate the relationship between structure and specificity and establish the mechanistic basis for β-lactam turnover in this enzyme family. In this review we collate recently published structural, kinetic, and mechanistic information on the interactions between clinically relevant β-lactam antibiotics and inhibitors with OXA-48 β-lactamases. Collectively, these studies are starting to form a detailed picture of the underlying bases for the differences in β-lactam specificity between OXA-48 variants, and the consequent differences in resistance phenotype. We focus specifically on aspects of carbapenemase and cephalosporinase activities of OXA-48 β-lactamases and discuss β-lactamase inhibitor development in this context. Throughout the review, we also outline key open research questions for future investigation.
Original languageEnglish
Article numbere00184
JournalAntimicrobial Agents and Chemotherapy
Volume65
Issue number6
Early online date22 Mar 2021
DOIs
Publication statusPublished - 18 May 2021

Bibliographical note

Funding Information:
Viivi H. A. Hirvonen is supported by the UK Medical Research Council (MR/N0137941/1 for the GW4 BioMed DTP awarded to the Universities of Bath, Bristol, Cardiff and Exeter). Marc W. van der Kamp is a BBSRC David Phillips Fellow and thanks the Biotechnology and Biological Sciences Research Council for funding (BB/M026280/1).

Publisher Copyright:
Copyright © 2021 American Society for Microbiology. All Rights Reserved.

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