A Mg2+-water bridge between the C-3, C-4 diketo moiety of fluoroquinolones and the conserved amino acid residues in the GyrA/ParC subunit is critical for the binding of a fluoroquinolone to a topoisomerase-DNA covalent complex. The fluoroquinolone UING-5-249 (249) can bind to the GyrB subunit through its C7-aminomethylpyrrolidine group. This interaction is responsible for enhanced activities of 249 against the wild type and quinolone-resistant mutant topoisomerases. To further evaluate the effects of the 249-GyrB interaction on fluoroquinolone activity, we examined the activities of decarboxy- and thio-249 against DNA gyrase and conducted docking studies using the structure of a gyrase-ciprofloxacin-DNA ternary complex. We found that the 249-GyrB interaction rescued the activity of thio-249 but not that of decarboxy-249. A C7-group that binds more strongly to the GyrB subunit may allow for modifications at the C-4 position, leading to a novel compound that is active against the wild type and quinolone-resistant pathogens.

中文翻译：

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C7-氨基甲基吡咯烷基团可挽救硫代氟喹诺酮的活性。

氟喹诺酮的C-3，C-4二酮部分与GyrA / ParC亚基中保守的氨基酸残基之间的Mg2 +-水桥对于氟喹诺酮与拓扑异构酶-DNA共价复合物的结合至关重要。氟喹诺酮UING-5-249（249）可以通过其C7-氨基甲基吡咯烷基与GyrB亚基结合。这种相互作用负责增强249对抗野生型和喹诺酮抗性突变体拓扑异构酶的活性。为了进一步评估249-GyrB相互作用对氟喹诺酮活性的影响，我们检查了脱羧基和硫代249对DNA促旋酶的活性，并使用了促旋酶-环丙沙星-DNA三元复合物的结构进行了对接研究。我们发现249-GyrB相互作用挽救了thio-249的活性，但没有拯救de羧基-249的活性。