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 <24 CPU hours, a >99% reduction, and do not require fitting against experimental data or significant parameterization. The computational assay reveals mechanistic details of β-lactam breakdown and should assist in evaluating emerging β-lactamase variants and developing new antibiotics.