Graduate School of Pharmaceutical Sciences, Chiba University.
HiLIFE (Institute of Biotechnology), University of Helsinki.
Chem Pharm Bull (Tokyo). 2021;69(12):1179-1183. doi: 10.1248/cpb.c21-00611.
Metallo-β-lactamases (MBLs) are significant threats to humans because they deteriorate many kinds of β-lactam antibiotics and are key enzymes responsible for multi-drug resistance of bacterial pathogens. As a result of in vitro screening, two compounds were identified as potent inhibitors of two kinds of MBLs: imipenemase (IMP-1) and New Delhi metallo-β-lactamase (NDM-1). The binding structure of one of the identified compounds was clarified by an X-ray crystal analysis in complex with IMP-1, in which two possible binding poses were observed. Molecular dynamics (MD) simulations were performed by building two calculation models from the respective binding poses. The compound was stably bound to the catalytic site during the simulation in one pose. The binding model between NDM-1 and the compound was constructed for MD simulation. Calculation results for NDM-1 were similar to those of IMP-1. The simulation suggested that the binding of the identified inhibitory compound was also durable in the catalytic site of NDM-1. The compound will be a sound basis for the development of the inhibitors for MBLs.
金属β-内酰胺酶（MBLs）对人类构成严重威胁，因为它们会破坏多种β-内酰胺抗生素，是导致细菌病原体多药耐药的关键酶。通过体外筛选，发现两种化合物可有效抑制两种 MBL：亚胺培南酶（IMP-1）和新德里金属β-内酰胺酶（NDM-1）。通过与 IMP-1 形成复合物的 X 射线晶体分析，阐明了其中一种鉴定化合物的结合结构，观察到两种可能的结合构象。通过从各自的结合构象构建两个计算模型，进行了分子动力学（MD）模拟。在一个构象中，该化合物在模拟过程中稳定地结合在催化部位。构建了 NDM-1 与该化合物的结合模型，用于 MD 模拟。NDM-1 的计算结果与 IMP-1 的结果相似。模拟表明，鉴定出的抑制化合物在 NDM-1 的催化部位的结合也是持久的。该化合物将为 MBL 抑制剂的开发提供良好的基础。
