一個DNA鏈運動的酶（如DNA和RNA聚合酶）在它們運動之前往往會引起超螺旋的積累。如果不加阻止,，這種積累會使DNA發(fā)生過度纏繞,，就像擰在一起的一個橡皮筋一樣。拓?fù)洚悩?gòu)酶通過首先解理,、然后降解DNA來緩解這種壓力,。拓?fù)洚悩?gòu)酶抑制因子被用作抗菌藥和抗癌藥，例如“喹諾酮”家族的抗菌藥自1962年以來一直在臨床上使用,，但目前它們的療效因能抗多種藥物的細(xì)菌的出現(xiàn)而打了折扣,。
現(xiàn)在，來自金黃葡萄球菌的DNA促旋酶（一種II-型拓?fù)洚悩?gòu)酶）的晶體結(jié)構(gòu),，已在與DNA和廣譜抗生素GSK299423形成的一種復(fù)合物中被確定,。這是一類新型抗生素的一個例子,，它們與跟“氟喹諾酮”相同的目標(biāo)發(fā)生相互作用，但在結(jié)構(gòu)上和機制上都與它們截然不同,。其結(jié)構(gòu)顯示了一個能夠繞開“氟喹諾酮”抗性的機制,，為探尋在臨床上已確認(rèn)目標(biāo)的不同抑制機制提供了一些策略。（生物谷Bioon.com）
原始出處：
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.
