Arhin Francis, Bélanger Odette, Ciblat Stéphane, Dehbi Mohammed, Delorme Daniel, Dietrich Evelyne, Dixit Dilip, Lafontaine Yanick, Lehoux Dario, Liu Jing, McKay Geoffrey A, Moeck Greg, Reddy Ranga, Rose Yannick, Srikumar Ramakrishnan, Tanaka Kelly S E, Williams Daniel M, Gros Philippe, Pelletier Jerry, Parr Thomas R, Far Adel Rafai
Targanta Therapeutics Inc, 7170 Frederick Banting, 2nd Floor, St. Laurent, Que., Canada H4S 2A1.
Bioorg Med Chem. 2006 Sep 1;14(17):5812-32. doi: 10.1016/j.bmc.2006.05.035. Epub 2006 Jun 8.
The RNA polymerase holoenzyme is a proven target for antibacterial agents. A high-throughput screening program based on this enzyme from Staphylococcus aureus had previously identified a 2-ureidothiophene-3-carboxylate as a low micromolar inhibitor. An investigation of the relationships between the structures of this class of compounds and their inhibitory- and antibacterial activities is described here, leading to a set of potent RNA polymerase inhibitors with antibacterial activity. Characterization of this bioactivity, including studies of the mechanism of action, is provided, highlighting the power of the reverse chemical genetics approach in providing tools to inhibit the bacterial RNA polymerase.
RNA聚合酶全酶是已证实的抗菌剂作用靶点。此前，一个基于金黄色葡萄球菌的这种酶开展的高通量筛选项目已鉴定出一种2-脲基噻吩-3-羧酸盐为低微摩尔浓度抑制剂。本文描述了对这类化合物的结构与其抑制活性和抗菌活性之间关系的研究，从而得到了一组具有抗菌活性的强效RNA聚合酶抑制剂。文中还提供了这种生物活性的表征，包括作用机制研究，突出了反向化学遗传学方法在提供抑制细菌RNA聚合酶工具方面的作用。
