Multiscale Simulations of Clavulanate Inhibition Identify the Reactive Complex in Class A beta-Lactamases and Predict the Efficiency of Inhibition

作者：Fritz Ruben A; Alzate Morales Jans H; Spencer James; Mulholland Adrian J; van der Kamp Marc W

来源：Biochemistry, 2018, 57(26): 3560-3563.

DOI：10.1021/acs.biochem.8b00480

Clavulanate is used as an effective drug in combination with beta-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 beta-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions identify the decarboxylated transenamine complex as being responsible for inhibition. Further, the obtained free energy barriers discriminate clinically relevant inhibition (TEM-l) from less effective inhibition (KPC-2).

• 出版日期2018-7-3
• 单位上海生物信息技术研究中心