Tuo Yan, Tang Yuelu, Yang Ran, Zhao XueMin, Luo Minghe, Zhou Xing, Wang Yuanqiang
School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China; Chongqing University Cancer Hospital, Chongqing 400030, China.
School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
Int J Biol Macromol. 2023 Oct 1;250:126109. doi: 10.1016/j.ijbiomac.2023.126109. Epub 2023 Aug 4.
The AdeABC efflux pump is an important mechanism causing multidrug resistance in Acinetobacter baumannii, and its main component AdeB can recognize carbapenems, aminoglycosides, and other multi-class antibiotics and efflux them intracellularly, which is an ideal target for the development of anti-multidrug resistant bacteria drugs. Here, we combined multiple computer-aided drug design methods to target AdeB to identify promising novel structural inhibitors. Virtual screening was performed by molecular docking and molecular dynamics simulation (MD) and 12 potential compounds were identified from the databases. Meanwhile, their biological activities were validated by in vitro activity assays, and ChemDiv L676-2179 (γ-IFN), ChemDiv L676-1461, and Chembridge 53717615 were confirmed to suppress efflux effects and restore antibiotic susceptibility of resistant bacteria, which are expected to be developed as adjuvant drugs for the treatment of multi-drug resistant Acinetobacter baumannii clinical infections.
AdeABC外排泵是鲍曼不动杆菌产生多重耐药性的重要机制，其主要成分AdeB可识别碳青霉烯类、氨基糖苷类等多类抗生素并将其胞内外排，是开发抗多重耐药菌药物的理想靶点。在此，我们结合多种计算机辅助药物设计方法针对AdeB来鉴定有前景的新型结构抑制剂。通过分子对接和分子动力学模拟（MD）进行虚拟筛选，从数据库中鉴定出12种潜在化合物。同时，通过体外活性测定验证了它们的生物活性，ChemDiv L676-2179（γ-干扰素）、ChemDiv L676-1461和Chembridge 53717615被证实可抑制外排效应并恢复耐药菌对抗生素的敏感性，有望开发成为治疗多重耐药鲍曼不动杆菌临床感染的辅助药物。
