DRUG TARGETING M. TUBERCULOSIS ARABINOSYL TRANSFERASES

描述(摘自申请者的摘要)：结核病仍然是主要的 世界范围内发病和死亡的原因，病例数量因 与艾滋病毒大流行和耐药菌株的出现有关。去战斗 这些问题更有效的抗生素必须开发得更好 药代动力学和毒性低于目前使用的药物。它是 本建议的目的是研究细菌的化学、生物化学和基因组学 结核分枝杆菌的阿拉伯糖代谢及一线药物的作用 乙胺丁醇对重要的霉菌多糖(MAG)生物合成的影响 卡斯卡德。MAG是一种独特的脂化多糖，对其具有保护和保护作用 来自宿主免疫系统的结核杆菌在那里找到了它的 进化的利基。参与MAG生物合成的蛋白质非常好。 药物靶标，因为它们对生物体的生长是必不可少的，而且 分枝杆菌所特有的。然而，对基因知识的根本缺乏 牵涉其中阻止了这些目标的发展。这项建议是由 先进的细胞壁模拟受体的合成及其研究进展 新的阿拉伯糖基转移酶分析。使用这些分析方法，可以确定 α(1-3)阿拉伯糖基转移酶活性与一线药物 乙胺丁醇将被定义。这些化验还将允许详细分析 β(1-2)阿拉伯糖基转移的机制及辅助鉴定 β(1-2)转移酶。编码embCAB操纵子的蛋白质在 将探索阿拉伯胶的生物合成及其对乙胺丁醇和乙胺丁醇的敏感性 检查了新的抗分枝杆菌药物。最重要的是，从 这些研究将启动一项彻底的药物化学努力，包括 这些目标的发展为新的、更有效和毒性更低的 针对结核病的治疗。

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.