Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: Intelligent design and evolution through the judicious use of structure-guided design and stucture-activity relationships
Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: Intelligent design and evolution through the judicious use of structure-guided design and stucture-activity relationships
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DOI：
10.1021/jm800318d
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发表时间：
2008-09-11
影响因子：
7.3
通讯作者：
Stamos, Dean
中科院分区：
文献类型：
--
作者：
Charifson, Paul S.;Grillot, Anne-Laure;Stamos, Dean
发现具有新的作用机制的新型抗菌剂对于克服影响所有目前使用的抗生素的细菌耐药性问题是必要的。细菌DNA旋切酶和拓扑异构酶IV是临床证实的氟喹诺酮类抗生素的靶点，它们通过抑制催化亚基发挥抗菌活性。通过与这些靶点的ATP位点相互作用来抑制这些靶点在临床上并不成功。本文介绍了一类新的低分子量合成的结合文件ATP位点的回转酶和拓扑异构酶抑制剂的发现和表征。苯并咪唑脲是两种酶的双靶向抑制剂，对引起医院和社区获得性感染的多种相关病原体具有有效的抗菌活性。通过使用结构导向设计、建模和结构-活性关系，描述了这类新型抗菌药物的发现和优化。在两种啮齿动物感染模型中，通过口服和静脉给药，研究了酶抑制、抗菌活性和体内疗效的数据。
The discovery of new antibacterial agents with novel mechanisms of action is necessary to overcome the problem of bacterial resistance that affects all Currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV are well-characterized clinically validated targets of the fluoroquinolone antibiotics which exert their antibacterial activity through inhibition of the catalytic Subunits. Inhibition of these targets through interaction with their ATP sites has been less clinically successful. The discovery and characterization of a new class of low molecular weight, synthetic inhibitors of gyrase and topoisomerase IV that bind to file ATP sites are presented. The benzimidazole ureas are dual targeting inhibitors of both enzymes and possess potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. The discovery and optimization of this novel class of antibacterials by the use of structure-guided design, modeling, and structure-activity relationships are described. Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models.