一个DNA链运动的酶（如DNA和RNA聚合酶）在它们运动之前往往会引起超螺旋的积累。如果不加阻止，这种积累会使DNA发生过度缠绕，就像拧在一起的一个橡皮筋一样。拓扑异构酶通过首先解理、然后降解DNA来缓解这种压力。拓扑异构酶抑制因子被用作抗菌药和抗癌药，例如“喹诺酮”家族的抗菌药自1962年以来一直在临床上使用，但目前它们的疗效因能抗多种药物的细菌的出现而打了折扣。
现在，来自金黄葡萄球菌的DNA促旋酶（一种II-型拓扑异构酶）的晶体结构，已在与DNA和广谱抗生素GSK299423形成的一种复合物中被确定。这是一类新型抗生素的一个例子，它们与跟“氟喹诺酮”相同的目标发生相互作用，但在结构上和机制上都与它们截然不同。其结构显示了一个能够绕开“氟喹诺酮”抗性的机制，为探寻在临床上已确认目标的不同抑制机制提供了一些策略。（生物谷Bioon.com）
原始出处：
Nature doi:10.1038/nature09197
Type IIA topoisomerase inhibition by a new class of antibacterial agents
Benjamin D. Bax,Pan F. Chan,Drake S. Eggleston,Andrew Fosberry,Daniel R. Gentry,Fabrice Gorrec,Ilaria Giordano,Michael M. Hann,Alan Hennessy,Martin Hibbs,Jianzhong Huang,Emma Jones,Jo Jones,Kristin Koretke Brown,Ceri J. Lewis,Earl W. May,Martin R. Saunders,Onkar Singh,Claus E. Spitzfaden,Carol Shen,Anthony Shillings,Andrew J. Theobald,Alexandre Wohlkonig,Neil D. Pearson& Michael N. Gwynn
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?? 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.
