Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, 208016, India.
Current Address: Lehrstuhl für Theoretische Chemie, Ruhr Universität Bochum, 44780, Bochum, Germany.
Chemistry. 2020 Aug 3;26(43):9639-9651. doi: 10.1002/chem.202001261. Epub 2020 Jul 9.
Disseminating antibiotic resistance rendered by bacteria against the widely used β-lactam antibiotics is a serious concern for public health care. The development of inhibitors for drug-resistant β-lactamase enzymes is vital to combat this rapidly escalating problem. Recently, the U.S. Food and Drug Administration approved a non-β-lactam inhibitor called avibactam for the treatment of complicated intra-abdominal and urinary tract infections caused by drug-resistant Gram-negative bacteria. This work sheds light on the molecular origin of the inhibitory effect of avibactam against the drug-resistant CTX-M variant of class A β-lactamases. In particular, we probed the structural evolution, dynamics features, and energetics along the acylation and deacylation reaction pathways through enhanced sampling molecular dynamics methods and free-energy calculations. We scrutinized the roles of active site residues, the nature of the carbamoyl linkage formed in the inhibitor-enzyme covalent intermediate, and other structural features of the inhibitor molecule. By unraveling the reasons behind the inhibition of all the deacylation routes, we can explain various experimental structural and kinetics data, and propose a way to design new inhibitors based on the β-lactam framework.
细菌对广泛使用的β-内酰胺类抗生素产生的耐药性的传播，是公共卫生保健领域的一个严重关切。开发针对耐药β-内酰胺酶的抑制剂对于应对这一迅速升级的问题至关重要。最近，美国食品和药物管理局批准了一种非β-内酰胺抑制剂阿维巴坦，用于治疗由耐药革兰氏阴性菌引起的复杂腹腔内和尿路感染。这项工作阐明了阿维巴坦抑制耐药 CTX-M 型 A 类β-内酰胺酶变体的抑制作用的分子起源。具体而言，我们通过增强采样分子动力学方法和自由能计算，探究了酰化和脱酰反应途径中的结构演化、动力学特征和能量学。我们仔细研究了活性位点残基的作用、抑制剂-酶共价中间体中形成的氨基甲酰键的性质以及抑制剂分子的其他结构特征。通过揭示所有脱酰途径抑制的原因，我们可以解释各种实验结构和动力学数据，并提出一种基于β-内酰胺框架设计新型抑制剂的方法。
