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

Jabeen, Hira; Beer, Michael; Spencer, James; van der Kamp, Marc W; Bunzel, H Adrian; Mulholland, Adrian J

Jabeen, Hira; Beer, Michael; Spencer, James; van der Kamp, Marc W; Bunzel, H Adrian; Mulholland, Adrian J.

Afiliación

Jabeen H; Centre for Computational Chemistry, School of Chemistry, University of Bristol, BS8 1TS Bristol, United Kingdom.
Beer M; Centre for Computational Chemistry, School of Chemistry, University of Bristol, BS8 1TS Bristol, United Kingdom.
Spencer J; School of Cellular and Molecular Medicine, University of Bristol, BS8 1TD Bristol, United Kingdom.
van der Kamp MW; School of Cellular and Molecular Medicine, University of Bristol, BS8 1TD Bristol, United Kingdom.
Bunzel HA; Centre for Computational Chemistry, School of Chemistry, University of Bristol, BS8 1TS Bristol, United Kingdom.
Mulholland AJ; School of Biochemistry, University of Bristol, BS8 1TD Bristol, United Kingdom.

ACS Catal ; 14(9): 7166-7172, 2024 May 03.

Article en En | MEDLINE | ID: mdl-38721371

ABSTRACT

ABSTRACT

Resistance to antibiotics is a public health crisis. Although carbapenems are less susceptible to resistance than other ß-lactam antibiotics, ß-lactamases mediating resistance against these drugs are spreading. Here, we dissect the contributions of electric fields to carbapenemase activity in class A ß-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.

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Catal Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos

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