Cunningham Mark L, Kwan Bryan P, Nelson Kirk J, Bensen Daniel C, Shaw Karen J
1Trius Therapeutics, Inc., San Diego, CA, USA.
J Biomol Screen. 2013 Oct;18(9):1018-26. doi: 10.1177/1087057113487208. Epub 2013 May 17.
The macromolecular synthesis assay was optimized in both S. aureus and E. coli imp and used to define patterns of inhibition of DNA, RNA, protein, and cell wall biosynthesis of several drug classes. The concentration of drug required to elicit pathway inhibition differed among the antimicrobial agents tested, with inhibition detected at concentrations significantly below the minimum inhibitory concentration (MIC) for tedizolid; within 4-fold of the MIC for ciprofloxacin, cefepime, vancomycin, tetracycline, and chloramphenicol; and significantly above the MIC for rifampicin and kanamycin. In a DNA gyrase/topoisomerase IV structure-based drug design optimization program, the assay rapidly identified undesirable off-target activity within certain chemotypes, altering the course of the program to focus on the series that maintained on-target activity.
在金黄色葡萄球菌和大肠杆菌中对大分子合成测定法进行了优化，并用于确定几种药物类别对DNA、RNA、蛋白质和细胞壁生物合成的抑制模式。引发途径抑制所需的药物浓度在测试的抗菌剂之间有所不同，替地唑胺在显著低于最低抑菌浓度（MIC）的浓度下检测到抑制作用；环丙沙星、头孢吡肟、万古霉素、四环素和氯霉素的抑制作用在MIC的4倍以内；利福平和平霉素的抑制作用则显著高于MIC。在基于DNA促旋酶/拓扑异构酶IV结构的药物设计优化程序中，该测定法迅速识别出某些化学类型中不良的脱靶活性，从而改变了程序的方向，使其专注于保持靶向活性的系列。
