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

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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.