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, H. Adrian Bunzel, Adrian J. Mulholland
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.