Jabeen Hira, Beer Michael, Spencer James, van der Kamp Marc W, Bunzel H Adrian, Mulholland Adrian J
Centre for Computational Chemistry, School of Chemistry, University of Bristol, BS8 1TS Bristol, United Kingdom.
School of Cellular and Molecular Medicine, University of Bristol, BS8 1TD Bristol, United Kingdom.
ACS Catal. 2024 Apr 23;14(9):7166-7172. doi: 10.1021/acscatal.3c05302. eCollection 2024 May 3.
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.
抗生素耐药性是一场公共卫生危机。尽管碳青霉烯类药物比其他β-内酰胺类抗生素更不易产生耐药性，但介导对这些药物耐药的β-内酰胺酶正在传播。在此，我们剖析电场对A类β-内酰胺酶中碳青霉烯酶活性的贡献。我们对美罗培南酰基酶水解进行了QM/MM分子动力学模拟，该模拟能够正确区分碳青霉烯酶。电场分析表明，去酰化过渡态和四面体中间体中的活性位点场是活性的重要决定因素。活性位点场确定了几个残基，其中一些位于远处，这些残基可区分高效碳青霉烯酶。我们的场分析脚本（www.github.com/bunzela/FieldTools）可能有助于理解和对抗抗生素耐药性。
