Mechanism of Ampicillin Hydrolysis by New Delhi Metallo-β-Lactamase 1: Insight From QM/MM MP2 Calculation

The New Delhi metallo-β-lactamase 1 (NDM-1) can hydrolyze nearly all clinically important β-lactam antibiotics, narrowing the options for effective treatment of bacterial infections. QM/MM MP2 calculations are performed to reveal the mechanism of ampicillin hydrolysis catalyzed by NDM-1. It is found...

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Bibliographic Details
Published in:Journal of computational chemistry 2025-01, Vol.46 (1), p.e27544
Main Authors: Lai, Rui, Li, Hui
Format: Article
Language:English
Subjects:
Ampicillin - chemistry
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
beta-Lactamases - chemistry
beta-Lactamases - metabolism
Hydrolysis
Quantum Theory
Thermodynamics
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Summary:The New Delhi metallo-β-lactamase 1 (NDM-1) can hydrolyze nearly all clinically important β-lactam antibiotics, narrowing the options for effective treatment of bacterial infections. QM/MM MP2 calculations are performed to reveal the mechanism of ampicillin hydrolysis catalyzed by NDM-1. It is found that the rate-determining step is the dissociation of hydrolyzed ampicillin from the NDM-1 active site, which requires a proton transfer from the bridging neutral water molecule to the newly formed carboxylate group. The precedent reaction steps, including the hydroxide nucleophilic addition, CN bond cleavage, and the protonation of the negative lactam N atom by a solvent water molecule, all require insignificant activation free energies. The calculated activation free energy for this rate-determining proton transfer step is 16.0 kcal/mol, in good agreement with experimental values of 13.7 ~ 14.7 kcal/mol. This proton transfer step exhibits a solvent hydrogen-deuterium kinetic isotope effect of 3.4, consistent with several experimental kinetic results.
ISSN:1096-987X
0192-8651
1096-987X
DOI:10.1002/jcc.27544