Issue 42, 2021

QM/MM modeling of class A β-lactamases reveals distinct acylation pathways for ampicillin and cefalexin

Abstract

Efficient mechanism-based design of antibiotics that are not susceptible to β-lactamases is hindered by the lack of comprehensive knowledge on the energetic landscapes for the hydrolysis of various β-lactams. Herein, we adopted efficient quantum mechanics/molecular mechanics simulations to explore the acylation reaction catalyzed by CTX-M-44 (Toho-1) β-lactamase. We show that the catalytic pathways for β-lactam hydrolysis are correlated to substrate scaffolds: using Glu166 as the only general base for acylation is viable for ampicillin but prohibitive for cefalexin. The present computational workflow provides quantitative insights to facilitate the optimization of future β-lactam antibiotics.

Graphical abstract: QM/MM modeling of class A β-lactamases reveals distinct acylation pathways for ampicillin and cefalexin

Supplementary files

Article information

Article type
Communication
Submitted
13 ago 2021
Accepted
07 out 2021
First published
07 out 2021

Org. Biomol. Chem., 2021,19, 9182-9189

Author version available

QM/MM modeling of class A β-lactamases reveals distinct acylation pathways for ampicillin and cefalexin

Z. Song, F. Trozzi, T. Palzkill and P. Tao, Org. Biomol. Chem., 2021, 19, 9182 DOI: 10.1039/D1OB01593A

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