NOVEL DRUG DEVELOPMENT STRATEGY FOR M TUBERCULOSIS

描述：（改编自研究者摘要）分枝杆菌 肺结核是世界上传染病造成死亡的主要原因， 第三世界，在美国急剧增加，主要是 因为艾滋病的流行。 菌株M.结核病已经出现 对许多抗结核药物有抗药性， 异烟肼和利福平。 Cubist Pharmaceuticals的目标是 氨酰-tRNA合成酶，一种参与 蛋白质合成，开发一种新型抗生素。 的tRNA 合成酶在进化过程中发生了显著的分化， 独特的序列和结构变异性， 用于物种特异性抑制的药物设计。 研究的目标 建议开发克隆和表达的药物筛选系统， M.结核病tRNA合成酶基因通过酶和全细胞测定。 分枝结核病基因将在细菌和/或酵母中表达 缺乏合适的tRNA合成酶的无效菌株。 这些 表达系统将作为方便的试验菌株进行筛选 小分子的潜在候选药物。 有效的抑制剂可以 随后针对平行测试者筛选特异性 人tRNA合成酶菌株。 人与M. 结核病tRNA合成酶将产生一个强大的候选药物， 结核病的治疗和控制。

DESCRIPTION: (adapted from investigator's abstract) Mycobacterium tuberculosis is a leading cause of death by infectious disease in the third world and is sharply increasing in the United States, primarily because of the AIDS epidemic. Strains of M. tuberculosis have emerged which are resistant to the many anti-tuberculosis drugs, including isoniazid and rifampicin. Cubist Pharmaceuticals is targeting the aminoacyl-tRNA synthetases, an essential family of enzymes involved in protein synthesis, to develop a novel class of antibiotics. The tRNA synthetases have significantly diverged through evolution, leading to distinct sequence and structural variabilities which facilitate rational drug design for species-specific inhibition. The goal of the research proposed is to develop drug-screening systems for cloned and expressed M. tuberculosis tRNA synthetase genes via enzyme and whole cell assays. The M. tuberculosis genes will be expressed in bacterial and/or yeast null strains which lack the appropriate tRNA synthetase. These expression systems will serve as convenient tester strains to screen small molecules for potential drug candidates. Effective inhibitors can be subsequently screened for specificity against a parallel tester strain for human tRNA synthetases. Discrimination of human and M. tuberculosis tRNA synthetases will yield a powerful drug candidate for the treatment and control of TB.