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 language | English |
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Pages (from-to) | 7166-7172 |
Number of pages | 7 |
Journal | ACS Catalysis |
Volume | 14 |
Issue number | 9 |
Early online date | 23 Apr 2024 |
DOIs | |
Publication status | Published - 3 May 2024 |
Bibliographical note
Publisher Copyright:© 2024 The Authors. Published by American Chemical Society.
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Alam, S. R. (Manager), Eccleston, P. E. (Other), Williams, D. A. G. (Manager) & Atack, S. H. (Other)
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