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X-TB


Tuberculosis

Structural and Functional Genomics of Mycobacterium Tuberculosis
Framework programme:
5
Project number:
QLK2-CT-2001-02018
EC contribution:
€ 2 299 631
Duration:
36 months
Type:
RS
Starting date:
1 January 2002
Website:
http://www.pasteur.fr/ip/easysite/pasteur/fr/themes-de-recherche-maladies/fiches-thematiques/tuberculose

Keywords: Protein structure; proteomics and linkage maps; chemical library screenings; rational design of inhibitors; bioinformatics; drug targets; comparative genomics; protein and nucleotide kinases; cytochromes P450; mycolic acid pathway

Summary:

The general objective of the X-TB project is to use an integrated, multidisciplinary approach combining proteomics with structural and functional genomics to define the proteome of the tubercle bacillus with the explicit aims of identifying novel drug targets and developing new chemotherapeutic compounds to treat tuberculosis.  Attempts will be made to identify lead compounds for new drugs that might help to reduce the duration of therapy through their greater potency and show activity against the current multidrug resistant strains of Mycobacterium tuberculosis.

Problem:

Given the current global socio-political climate, the importance of curing and preventing tuberculosis cannot be overstated. While the development of a new vaccine to replace BCG is a laudable if long-term objective, the design of new drugs is a more tangible goal. Although directly observed short-course chemotherapy (DOTS) exists to treat the disease, this treatment has not been improved for over 30 years. DOTS is singularly inefficient by the standards of today’s pharmaceutical industry in terms of drug activity and toxicity, and its efficacy is threatened by increasingly widespread drug resistance. The consortium wishes to employ state-of-the-art post-genomics technology to initiate the development of enhanced tuberculosis chemotherapy for the new millennium. In particular, they would like to harness the powerful new tools of structural and functional genomics for drug and drug target discovery.

Aim:

The principal objective is to further the development of new drugs to combat the growing menace of tuberculosis by using a post-genomics approach. The proteome of Mycobacterium tuberculosis will be intensively studied to expand the knowledge base and identify proteins or enzymes that could serve as targets for new antibiotics. Essentiality will be determined by creating appropriate mutants and specificity appraised by bioinformatics. Mycobacterial proteins that could serve as novel targets for chemotherapy will be identified, and inhibitors will either be isolated from libraries using novel screens of natural or (semi)synthetic products or, by using three-dimensional  structures as templates for drug design.

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