Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Future Med Chem. 2018 May 1;10(10):1207-1227. doi: 10.4155/fmc-2017-0257. Epub 2018 May 22.
New antibacterials that modulate less explored targets are needed to fight the emerging bacterial resistance. DNA gyrase and topoisomerase IV are attractive targets in this search. These are both type II topoisomerases that can cleave both DNA strands, and can thus alter DNA topology during replication or similar processes. Currently, there are no ATP-competitive inhibitors of these two enzymes on the market, as the only aminocoumarin representative, novobiocin, was withdrawn due to safety concerns. The search for novel ATP-competitive inhibitors is a focus of ongoing industrial and academical research. This review summarizes the recent efforts in the design, synthesis and evaluation of GyrB/ParE inhibitors. The various approaches to achieve improved antibacterial activities are described, with particular reference to Gram-negative bacteria.
需要寻找新的、作用于较少研究靶点的抗菌药物来对抗日益严重的细菌耐药性。在这种情况下，DNA 拓扑异构酶 II 和拓扑异构酶 IV 是极具吸引力的靶标。这两种酶均属于 II 型拓扑异构酶，可以同时切割两条 DNA 链，因此可以在复制或类似过程中改变 DNA 拓扑结构。目前，市场上还没有针对这两种酶的 ATP 竞争性抑制剂，因为唯一的氨基香豆素类药物新生霉素由于安全性问题已被撤出市场。寻找新型 ATP 竞争性抑制剂是当前工业界和学术界研究的重点。本文综述了近年来在设计、合成和评估 GyrB/ParE 抑制剂方面的最新进展。文中描述了为提高抗菌活性而采用的各种方法，并特别提到了革兰氏阴性菌。
