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Multiscale Simulations of Clavulanate Inhibition Identify the Reactive Complex in Class A β-Lactamases and Predict the Efficiency of Inhibition
- Fritz, Rubén A., Alzate-Morales, Jans H., Spencer, James, Mulholland, Adrian J., van der Kamp, Marc W.
- Biochemistry 2018 v.57 no.26 pp. 3560-3563
- Gibbs free energy, antibiotic resistance, bacteria, beta-lactam antibiotics, beta-lactamase, drugs, quantum mechanics
- Clavulanate is used as an effective drug in combination with β-lactam antibiotics to treat infections of some antibiotic resistant bacteria. Here, we perform combined quantum mechanics/molecular mechanics simulations of several covalent complexes of clavulanate with class A β-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions identify the decarboxylated trans-enamine complex as being responsible for inhibition. Further, the obtained free energy barriers discriminate clinically relevant inhibition (TEM-1) from less effective inhibition (KPC-2).