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

Efficient mechanism-based design of antibiotics that are not susceptible to beta-lactamases is hindered by the lack of comprehensive knowledge on the energetic landscapes for the hydrolysis of various beta-lactams. Herein, we adopted efficient quantum mechanics/molecular mechanics simulations to explore the acylation reaction catalyzed by CTX-M-44 (Toho-1) beta-lactamase. We show that the catalytic pathways for beta-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 beta-lactam antibiotics.

Automated summary

This study utilized efficient computational methods to investigate the acylation reaction catalyzed by CTX-M-44 (Toho-1) beta-lactamase, revealing that the catalytic pathways for beta-lactam hydrolysis are substrate-dependent. The findings offer quantitative insights to aid in the optimization of future beta-lactam antibiotics.