DRUG TARGETING M. TUBERCULOSIS ARABINOSYL TRANSFERASES

描述（改编自申请人的摘要）：结核病仍然是一个主要的 全球发病率和死亡率的原因，病例数因 艾滋病的流行和抗药性菌株的出现。打击 这些问题必须开发出更有效的抗生素， 药物代谢动力学和较低的毒性比目前使用的药物。是 这项建议的目的是研究化学，生物化学和基因组学， M.结核病和一线药物的影响 乙胺丁醇对重要的菌酰阿拉伯半乳聚糖（MAG）生物合成的影响 级联。MAG是一种独特的脂化多糖， 从宿主免疫系统中分离结核杆菌， 进化生态位与MAG生物合成有关的蛋白质是极好的 药物靶点，因为它们对生物体的生长至关重要， 分枝杆菌特有的然而，对基因的基本知识缺乏 这些目标的实现，阻碍了这些目标的实现。该提案发起 先进的细胞壁模拟受体的合成和发展， 新的阿拉伯糖基转移酶测定。使用这些测定， α（1-3）阿拉伯糖基转移酶活性和一线药物 将定义乙胺丁醇。这些测定还将允许详细分析 β（1-2）阿拉伯糖基转移的机制，并有助于鉴定 β（1-2）转移酶。编码embCAB操纵子的蛋白质在 阿拉伯聚糖的生物合成将被探索，其敏感性乙胺丁醇和 新的抗分枝杆菌检查。最重要的是，从 这些研究将启动一项彻底的药物化学工作， 开发新的、更有效的、毒性更小的 治疗肺结核。

DESCRIPTION (adapted from applicant's abstract): Tuberculosis is still a major cause of morbidity and mortality worldwide with the number of cases rising due to the HIV pandemic and the emergence of drug resistant strains. To combat these problems more effective antibiotics must be developed with better pharmacokinetics and lower toxicity than the drugs currently used. It is the aim of this proposal to study the chemistry, biochemistry and genomics of arabinose metabolism in M. tuberculosis and the effects of the front line drug ethambutol on the important mycoloylarabinogalactan (MAG) biosynthetic cascade. MAG is a unique lipidated polysaccharide surrounding and protecting the tubercular bacilli from the host immune system where it has found its evolutionary niche. The proteins involved in MAG biosynthesis are excellent drug targets because they are essential for growth of the organism and are unique to mycobacteria. However, a fundamental lack of knowledge of the genes involved prevents these targets from being developed. This proposal initiates the synthesis of advanced cell wall mimetic acceptors and the development of new arabinosyl transferase assays. Using these assays the relationship between the alpha (1-3) arabinosyl transferase activity and the frontline drug ethambutol will be defined. These assays will also allow detailed analysis of the mechanism of beta (1-2) arabinosyl transfer and aid in identification of the beta (1-2) transferase. The role of the protein encoded embCAB operon in arabinan biosynthesis will be explored, and its sensitivity to ethambutol and novel antimycobacterials examined. Most importantly the knowledge gained from these studies will initiate a thorough medicinal chemistry effort involving these targets for the development of new, more effective and less toxic treatments against tuberculosis.