Inactivating tolC in multidrug-resistant Escherichia coli with differing sequence types and quinolone resistance-determining mutations reveals remarkably potentiated activity of the first-in-class topoisomerase inhibitors gepotidacin and zoliflodacin. Differences between both structurally unrelated compounds in comparison to fluoroquinolones regarding the selectivity of E. coli RND (resistance-nodulation-cell division)-type transporters, efflux inhibitors, and AcrB porter domain mutations were demonstrated. The findings should reinforce efforts to develop efflux-bypassing drugs and provide AcrB targets with critical relevance for this purpose.

中文翻译：

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新型拓扑异构酶抑制剂：评估 Gepotidacin 和 Zoliflodacin 在抗氟喹诺酮类大肠杆菌中对 tolC 灭活的效力并区分其外排泵底物性质

在具有不同序列类型和喹诺酮耐药性决定突变的多重耐药大肠杆菌中灭活tolC揭示了一流的拓扑异构酶抑制剂gepotidacin 和zoliflodacin 的显着增强活性。与氟喹诺酮类相比，两种结构无关的化合物在大肠杆菌RND（抗性结节细胞分裂）型转运蛋白、外排抑制剂和 AcrB 转运蛋白结构域突变的选择性方面存在差异。研究结果应加强开发绕过外排药物的努力，并为此目的提供具有关键相关性的 AcrB 靶点。