Type IIA topoisomerase inhibition by a new class of antibacterial agents
Type IIA topoisomerase inhibition by a new class of antibacterial agents
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DOI：
10.1038/nature09197
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发表时间：
2010-08-19
期刊：
影响因子：
64.8
通讯作者：
Gwynn, Michael N.
中科院分区：
文献类型：
--
作者：
Bax, Benjamin D.;Chan, Pan F.;Gwynn, Michael N.
尽管基因组学在识别新的基本细菌基因方面取得了成功，但在抗菌药物发现方面缺乏可持续的领导，以解决日益增长的多药耐药性问题。IIA型拓扑异构酶是一类主要的抗菌和抗癌药物靶点，但目前尚无成熟的结构基础来理解药物的作用。在这里，我们报道了一种有效的、新型的广谱抗菌剂与金黄色葡萄球菌DNA旋转酶和DNA的复合体的2.1埃晶体结构，显示了一种新的抑制模式，绕过了这个临床上重要的药物靶点的氟喹诺酮耐药性。该抑制剂在GyrA二聚体界面的两重轴上连接DNA和一个瞬时的非催化口袋，并靠近活性部位和氟喹诺酮类药物结合部位。在抑制剂复合体中，活性部位似乎准备切割DNA，在TOPRIM(拓扑异构酶/底物酶)结构域和剪刀状磷酸之间观察到单一的金属离子。这项工作为拓扑异构酶的作用机制提供了新的见解，并为基于结构的药物设计提供了平台，以对抗临床证明的但构象灵活的酶类的新型抗菌剂。
Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 angstrom crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor 'bridges' the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class.