An Efficient Computational Assay for β‑Lactam Antibiotic Breakdown by Class A β‑Lactamases

Class A β-lactamases cause clinically relevant resistance to β-lactam antibiotics. Carbapenem degradation is a particular concern. We present an efficient QM/MM molecular simulation protocol that accurately predicts the activity of β-lactamases against carbapenems. Simulations take less than 24 CPU...

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Bibliographic Details
Published in:Journal of chemical information and modeling 2019-08, Vol.59 (8), p.3365-3369
Main Authors: Hirvonen, Viivi H. A, Hammond, Katharine, Chudyk, Ewa I, Limb, Michael A. L, Spencer, James, Mulholland, Adrian J, van der Kamp, Marc W
Format: Article
Language:English
Subjects:
Amides
Anti-Bacterial Agents - metabolism
Antibiotics
beta-Lactamases - chemistry
beta-Lactamases - metabolism
beta-Lactams - metabolism
Breakdown
Computer simulation
Molecular Dynamics Simulation
Parameterization
Protein Conformation
Thermodynamics
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Summary:Class A β-lactamases cause clinically relevant resistance to β-lactam antibiotics. Carbapenem degradation is a particular concern. We present an efficient QM/MM molecular simulation protocol that accurately predicts the activity of β-lactamases against carbapenems. Simulations take less than 24 CPU hours, a greater than 99% reduction, and do not require fitting against experimental data or significant parametrization. This computational assay also reveals mechanistic details of β-lactam breakdown and should assist in evaluating emerging β-lactamase variants and developing new antibiotics.
ISSN:1549-9596
1549-960X
DOI:10.1021/acs.jcim.9b00442