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: 6235353
• 负责人: IAN CHOPRA
• 金额: $ 12.66万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6235353
• 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.

该研究项目目前正在 SmithKline Beecham (SB) 进行， 英国萨里市布罗克汉姆公园 (Brockham Park)，现已正式成为 NCDDG 的一部分 C0=操作协议，由项目负责人 I. Chopra 博士于 与英国其他参与的 SB 工作人员一起。 分枝杆菌细胞包膜含有大量复杂的物质 脂质和碳水化合物，特别是分枝菌酸、阿拉伯半乳聚糖和 脂阿拉伯甘露聚糖是这些生物体的高度特征。这 为新化疗药物的开发提供了一个有吸引力的目标 代理。 控制生物合成的基本机制 阿拉伯半乳聚糖、脂阿拉伯甘露聚糖和霉菌酸现已 充分理解新颖的目标导向的设计 干预策略是可行的。 因此，建议 在此计划期间，CS 工作人员将遵循一些 具体途径集中于抑制霉菌酸生物合成。 更多的 具体来说，他们将： (i) 基于 14C- 优化主屏幕 醋酸盐公司，（ii）开发第二代和第三代屏幕 与项目 1 和 2 结合使用部分纯化或纯化 蛋白质。 对化合物库进行评估并 SB 的新型霉菌酸抑制剂的天然产物来源 生物合成，(iii) 开发和利用结核分枝杆菌感染模型， (iv) 制定并实施全细胞和 BACTEC 筛选方案，(v) 为项目2提供蛋白质分析和克隆策略方面的支持， 最后，(vi) 探索 X 射线晶体学的可能用途/ 分子建模有助于开发新的治疗方法 抗结核分枝杆菌的药物。 在这个产业界的共同努力下 财团与我们学术界的同事一起应提供 与现有药物相结合的新产品，应允许 更有效地治疗结核病。