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

被引：14

作者：

Fritz, Ruben A. ^{[1
]}

Alzate-Morales, Jans H. ^{[1
]}

Spencer, James ^{[2
]}

Mulholland, Adrian J. ^{[3
]}

van der Kamp, Marc W. ^{[3
,4
]}

机构：

[1] Univ Talca, Fac Engn, Ctr Bioinformat & Mol Simulat, Talca, Chile

[2] Univ Bristol, Sch Cellular & Mol Med, Bristol BS8 1TD, Avon, England

[3] Univ Bristol, Sch Chem, Ctr Computat Chem, Bristol BS8 1TS, Avon, England

[4] Univ Bristol, Sch Biochem, Bristol BS8 1TD, Avon, England

来源：

BIOCHEMISTRY | 2018年 / 57卷 / 26期

基金：

英国工程与自然科学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

ANTIBIOTIC-RESISTANCE; COVALENT INHIBITORS; QM/MM; INTERMEDIATE; TAZOBACTAM; HYDROLYSIS; MECHANISMS; AVIBACTAM;

D O I：

10.1021/acs.biochem.8b00480

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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).

引用

页码：3560 / 3563

页数：4

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