NOVEL DRUG DEVELOPMENT STRATEGY FOR M TUBERCULOSIS

描述：(改编自调查人员摘要)分枝杆菌 结核病是我国传染病致死的主要原因之一。 第三世界，在美国急剧增加，主要是 因为艾滋病的流行。已经出现了结核分枝杆菌菌株 它们对许多抗结核病药物都有抗药性，包括 异烟肼和利福平。立体主义制药公司的目标是 氨酰-tRNA合成酶是一种重要的酶家族，参与了 蛋白质合成，开发一类新型抗生素。TRNA 合成酶在进化过程中出现了显著的分化，导致 不同的序列和结构变量，有助于理性 针对物种特异性抑制的药物设计。这项研究的目的 建议开发用于克隆和表达的药物筛选系统 酶法和全细胞法检测结核分枝杆菌tRNA合成酶基因。 结核分枝杆菌的基因将在细菌和/或酵母中表达。 缺乏适当tRNA合成酶的菌株为空。这些 表达系统将作为方便的测试菌株进行筛选 潜在候选药物的小分子。有效的抑制剂可以 随后对平行测试仪进行特异性筛选 人tRNA合成酶的菌株。人与人的区别。 结核分枝杆菌tRNA合成酶将产生一种强有力的候选药物 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.