Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.

中文翻译：

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解决革兰氏阴性细菌中氟喹诺酮耐药性的拓扑异构酶抑制剂。

自从五十年前发现喹诺酮类抗生素以来，作为广谱药物，已经取得了巨大成功，它通过双重抑制细菌DNA促旋酶和拓扑异构酶IV发挥其活性。在GyrA / ParC喹诺酮耐药性确定区域中，基于靶点的突变在很大程度上推动了耐药率的上升，侵蚀了其实用性，并威胁了这一至关重要的抗生素类药物的未来使用。本文中，我们描述了一系列4-（氨基甲基）喹啉-2（1 H）-one的发现和优化，以34为例，它们抑制细菌DNA促旋酶和拓扑异构酶IV并显示出对环丙沙星耐药的革兰氏阴性病原体的有效活性。X射线晶体学分析表明34 在拓扑异构酶IV-DNA裂解复合物中占据经典的喹诺酮结合位点，但是不与喹诺酮抗性确定区域中的残基形成显着接触。