Electric Fields Are a Key Determinant of Carbapenemase Activity in Class A β-Lactamases

Hira Jabeen, Michael Beer, James Spencer, Marc W Van der Kamp, Adrian A Bunzel*, Adrian J Mulholland*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

3 Citations (Scopus)

Abstract

Resistance to antibiotics is a public health crisis. Although carbapenems are less susceptible to resistance than other β-lactam antibiotics, β-lactamases mediating resistance against these drugs are spreading. Here, we dissect the contributions of electric fields to carbapenemase activity in class A β-lactamases. We perform QM/MM molecular dynamics simulations of meropenem acyl-enzyme hydrolysis that correctly discriminate carbapenemases. Electric field analysis shows that active-site fields in the deacylation transition state and tetrahedral intermediate are important determinants of activity. The active-site fields identify several residues, some distal, that distinguish efficient carbapenemases. Our field analysis script (www.github.com/bunzela/FieldTools) may help in understanding and combating antibiotic resistance.
Original languageEnglish
Pages (from-to)7166-7172
Number of pages7
JournalACS Catalysis
Volume14
Issue number9
Early online date23 Apr 2024
DOIs
Publication statusPublished - 3 May 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.

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