Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Sichuan, 610041, China.
State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
Eur J Med Chem. 2022 Jan 15;228:113965. doi: 10.1016/j.ejmech.2021.113965. Epub 2021 Nov 2.
Production of metallo-β-lactamases (MBLs) in bacterial pathogens is an important cause of resistance to the 'last-resort' carbapenem antibiotics. Development of effective MBL inhibitors to reverse carbapenem resistance in Gram-negative bacteria is still needed. We herein report X-ray structure-guided optimization of 1H-imidazole-2-carboxylic acid (ICA) derivatives by considering how to engage with the active-site flexible loops and improve penetration into Gram-negative bacteria. Structure-activity relationship studies revealed the importance of appropriate substituents at ICA 1-position to achieve potent inhibition to class B1 MBLs, particularly the Verona Integron-encoded MBLs (VIMs), mainly by involving ingenious interactions with the flexible active site loops as observed by crystallographic analyses. Of the tested ICA inhibitors, 55 displayed potent synergistic antibacterial activity with meropenem against engineered Escherichia coli strains and even intractable clinically isolated Pseudomonas aeruginosa producing VIM-2 MBL. The morphologic and internal structural changes of bacterial cells after treatment further demonstrated that 55 crossed the outer membrane and reversed the activity of meropenem. Moreover, 55 showed good pharmacokinetic and safety profile in vivo, which could be a potential candidate for combating VIM-mediated Gram-negative carbapenem resistance.
金属β-内酰胺酶（MBLs）在细菌病原体中的产生是导致对“最后手段”碳青霉烯类抗生素产生耐药性的重要原因。仍然需要开发有效的 MBL 抑制剂来逆转革兰氏阴性菌对碳青霉烯类抗生素的耐药性。本文报告了通过考虑如何与活性位点的柔性环结合并改善对革兰氏阴性菌的穿透性，对 1H-咪唑-2-羧酸（ICA）衍生物进行 X 射线结构引导优化。结构-活性关系研究表明，ICA 1-位适当取代基的重要性，以实现对 B1 类 MBL ，特别是 Verona 整合子编码的 MBL（VIM）的有效抑制，主要是通过晶体学分析观察到与柔性活性位点环的巧妙相互作用。在所测试的 ICA 抑制剂中，55 与美罗培南对工程化的大肠杆菌菌株表现出强大的协同抗菌活性，甚至对产生 VIM-2 MBL 的临床上难以治疗的铜绿假单胞菌也有作用。细菌细胞在处理后的形态和内部结构变化进一步证明，55 穿过外膜并逆转了美罗培南的活性。此外，55 在体内表现出良好的药代动力学和安全性特征，可能是对抗 VIM 介导的革兰氏阴性碳青霉烯类耐药性的潜在候选药物。
