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: 3727835
• 负责人: IAN CHOPRA
• 金额: --
• 依托单位: COLORADO STATE UNIVERSITY
• 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/3727835
• 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公司进行，