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  1. Resistance to carbapenem β-lactams presents major clinical and economical challenges for the treatment of pathogen infections. The fast hydrolysis of carbapenems by carbapenemase-producing bacterial strains enables the effective deactivation of carbapenem antibiotics. In this study, we aim to unravel the structural features that distinguish the notable deacylation activity of carbapenemases. The deacylation reactions between imipenem (IPM) and the KPC-2 class A serine-based β-lactamases (ASβLs) are modeled with combined quantum mechanical/molecular mechanical (QM/MM) minimum energy pathway (MEP) calculations and interpretable machine-learning (ML) methods. We first applied a dual-level computational protocol to achieve fast sampling of QM/MM MEPs. A tree-based ensemble ML model was employed to learn the MEP activation barriers from the conformational features of the KPC-2/IPM active site. The barrier-predicting model was then unboxed using the Shapley additive explanation (SHAP) importance attribution methods to derive mechanistic insights, which were also verified by additional QM/MM wavefunction analysis. Essentially, we show that potential hydrogen bonding interactions of the general base and the tautomerization states of the carbapenem pyrroline ring could concertedly regulate the activation barrier of KPC-2/IPM deacylation. Nonetheless, we demonstrate the efficacy of interpretable ML to assist the analysis of QM/MM simulation data for robust extraction of human-interpretable mechanistic insights.
    Free, publicly-accessible full text available January 4, 2024
  2. 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.