MYCOBACTERIAL CELL ENVELOPE--A TARGET FOR NOVEL DRUGS AGAINST TUBERCULOSIS

分枝杆菌细胞包膜——抗结核病新药的靶标

• 批准号: 5205864
• 负责人: IAN CHOPRA
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5205864
• 关键词: Mycobacterium; Mycobacterium smegmatis; Mycobacterium tuberculosis; antitubercular agents; cell free system; cell wall; chemical synthesis; clone cells; combination chemotherapy; disease /disorder model; drug design /synthesis /production; drug resistance; drug screening /evaluation; enzyme inhibitors; fatty acid biosynthesis; genetic strain; high performance liquid chromatography; hydroxy fatty acid; isoniazid; laboratory mouse; macrophage; microorganism culture; nonhuman therapy evaluation; protein sequence

This research program, currently under way at SmithKline Beecham (SB), Brockham Park, Surrey, England, which is now formally part of this NCDDG C0=operative Agreement, was written by the Project Leader, Dr. I. Chopra in conjunction with other participating SB staff in the United Kingdom. The mycobacterial cell envelope, which contains large amounts of complex lipids and carbohydrates, notably the mycolic acids, arabinogalactan and lipoarabinomannan, is highly characteristic of these organisms.This presents an attractive target for the development of new chemotherapeutic agents. The underlying mechanisms governing the biosynthesis of arabinogalactan, lipoarabinomannan and the mycolic acids are now sufficiently well understood that the design of novel target-directed intervention strategies is feasible. As a result, it is proposed that during the course of this program, CS staff will follow a number of concrete avenues focused on inhibition of mycolate biosynthesis. More specifically, they will: (i) optimize the primary screen based on 14C- acetate incorporation, (ii) develop second and third generation screens in conjunction with Projects 1 and 2 using partially purified or purified proteins. Conduct an evaluation of the chemical compounds library and natural product sources at SB for novel inhibitors of mycolate biosynthesis, (iii) develop and utilize M. tuberculosis infection models, (iv) develop and implement whole-cell and BACTEC screening protocols, (v) provide support to Project 2 in protein analysis and cloning strategies, and finally, (vi) exploit the possible use of X-ray crystallography/ molecular modelling as an aid in the development of novel therapeutic agents against M. tuberculosis. The combined efforts of this industrial consortium in conjunction with our colleagues from academia should provide novel products which, in combination with existing drugs, should allow for a more effective treatment of tuberculosis.

该研究计划目前正在Smithkline Beecham（SB）， 英格兰萨里的布罗克汉姆公园，现在正式的NCDDG C0 =手术协议，由项目负责人I. Chopra博士撰写 与英国其他参与的SB员工共同。 分枝杆菌细胞包膜，其中包含大量复合物 脂质和碳水化合物，尤其是霉菌酸，阿拉伯乳糖酸和碳水化合物 脂肪动瘤，是这些生物的高度特征。 为开发新的化学治疗性提供了一个有吸引力的目标 代理商。 控制生物合成的基本机制 阿拉伯那麦，脂脂瘤和麦芽酸现在是 充分理解了新型目标定向的设计 干预策略是可行的。 结果，有人提出 在此计划的过程中，CS员工将遵循许多 混凝土大道的重点是抑制霉菌性生物合成。 更多的 具体而言，它们将：（i）基于14C-优化主屏幕 乙酸盐融合，（ii）在 使用部分纯化或纯化的项目1和2结合 蛋白质。 进行化学化合物库的评估和 SB的天然产品来源用于新型霉菌酸盐的抑制剂 生物合成，（iii）开发和利用结核分枝杆菌感染模型， （iv）开发和实施全细胞和BACTEC筛选协议，（v） 在蛋白质分析和克隆策略中为项目2提供支持， 最后，（vi）利用X射线晶体学/ 分子建模作为新型治疗的发展 反对结核分枝杆菌的药物。 这个工业的综合努力 与学术界的同事一起，财团应提供 新产品，结合现有药物应允许 对结核病的更有效治疗。