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.

这项研究计划，目前正在进行的SmithKline Beecham（SB）， 英国萨里郡布罗克汉姆公园，现在正式成为NCDDG的一部分 C 0 =有效协议，由项目负责人I.乔普拉因 与联合王国其他参与SB的工作人员一起。 分枝杆菌的细胞被膜含有大量的复合物， 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 为开发新的化疗药物提供了一个有吸引力的靶点 剂. 生物合成的潜在机制 阿拉伯半乳聚糖、脂阿拉伯甘露聚糖和分枝菌酸现在 充分理解，设计新的靶向 干预措施是可行的。 因此，建议 在该计划的过程中，CS工作人员将遵循一些 具体途径集中在抑制霉菌酸生物合成上。 更 具体而言，他们将：（一）优化基于14 C的初级屏幕- （ii）开发第二代和第三代筛选， 与项目1和2结合使用部分纯化或纯化的 proteins. 对化合物库进行评估， SB的天然产物来源用于新型霉菌酸盐抑制剂 （iii）开发利用M.结核病感染模型， (iv)制定和实施全细胞和BACTEC筛选方案，（v） 在蛋白质分析和克隆策略方面为项目2提供支持， 最后，（vi）利用X射线晶体学的可能用途/ 分子模拟作为开发新的治疗药物的辅助手段 代理商对M。结核 这一行业的共同努力 联合会与我们的学术界同事一起， 与现有药物联合使用的新产品应允许 更有效地治疗肺结核。