The quinolone class of inhibitors of bacterial type II topoisomerases has gained major clinical importance during the last years due to improvements in both pharmacokinetic and pharmacodynamic properties. These include favorable bioavailability allowing oral administration, good tolerability, high tissue concentrations as well as superior bactericidal activity against a broad spectrum of clinically relevant pathogens, like enterobacteria, Pseudomonas aeruginoso, Staphylococcus aureus, and Streptococcus pneumoniae. In addition, no enzymatic mechanism of drug inactivation exists in bacteria and no indications for transfer of clinically relevant resistance exist. Nevertheless, resistance is being increasingly reported, even for naturally highly susceptible species like Escherichia coli. The underlying mechanisms of resistance include alterations in both bacterial targets, DNA gyrase and topoisomerase IV, often combined with mutations affecting drug accumulation, e.g., by increased drug efflux, reduced drug influx, or both. Investigations aiming at understanding the molecular mechanisms of quinolone action and resistance in more detail should provide a basis for a rational design of more potent derivatives. In addition, a prudent use of these highly valuable "magic bullets" is necessary to preserve their potential for the future.

中文翻译：

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细菌拓扑异构酶抑制剂：作用机制和耐药性以及临床方面。

近年来，由于药代动力学和药效学性质的改善，喹诺酮类II型细菌拓扑异构酶抑制剂已获得重要的临床意义。这些包括允许口服给药的良好生物利用度，良好的耐受性，较高的组织浓度以及对多种临床相关病原体（如肠杆菌，铜绿假单胞菌，金黄色葡萄球菌和肺炎链球菌）的优异杀菌活性。另外，细菌中不存在药物灭活的酶促机制，并且不存在转移临床相关耐药性的迹象。然而，即使对于自然高度易感的物种（如大肠杆菌），耐药性也越来越多。耐药的潜在机制包括细菌靶标，DNA促旋酶和拓扑异构酶IV的改变，通常与影响药物蓄积的突变（例如，通过增加药物外排量，减少药物流入或同时通过这两者）结合在一起。旨在更详细地了解喹诺酮作用和耐药的分子机制的研究应为合理设计更有效的衍生物提供基础。此外，必须谨慎使用这些极有价值的“魔术子弹”，以保留其未来的潜力。旨在更详细地了解喹诺酮作用和耐药的分子机制的研究应为合理设计更有效的衍生物提供基础。此外，必须谨慎使用这些极有价值的“魔术子弹”，以保留其未来的潜力。旨在更详细地了解喹诺酮作用和耐药的分子机制的研究应为合理设计更有效的衍生物提供基础。此外，必须谨慎使用这些极有价值的“魔术子弹”，以保留其未来的潜力。