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X-TB
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/X-TB/
Graphic element Structural and Functional Genomics of Mycobacterium Tuberculosis
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.

Expected results:

  1. Biochemically and structurally characterised potential drug targets of known function.
  2. High-throughput production of unknown proteins for library screening and structural studies.
  3. Function predictions and refined protein families from advanced bioinformatics.
  4. Definition of the proteome under different physiological conditions.
  5. Linkage maps for intraproteome and host-pathogen protein-protein interactions.
  6. Databases for proteomics and structural genomics.
  7. Confirmation of essentiality by gene replacement.
  8. Protein structures determined by NMR and X-ray crystallography.
  9. Novel automated screens using fluorescent two-hybrid systems.
  10. Screens of chemical and natural product libraries to identify potential lead compounds.
  11. Leads for drugs from rational design and molecular modelling.

Potential applications:

This project will lead to better definition of the proteins present in M. tuberculosis together with detailed understanding of their activities, regulation, structures and interactions. It is probable that many of these proteins play essential roles and therefore represent attractive drug targets. Screening of chemical and natural product libraries will identify potential ligands and inhibitors that could correspond to lead compounds for the development of new drugs to treat tuberculosis in all its forms.

Coordinator:

Stewart T. Cole
Unité de Génétique Moléculaire Bactérienne,
Institut Pasteur
25-28, rue du Docteur Roux,
75724 Paris Cedex 15
France
Tel: +33 1 45 68 84 46
Fax: +33 1 40 61 35 83
E-mail: stcole@pasteur.fr
Website: http://www.pasteur.fr/recherche/unites/Lgmb/

Partners:


Principal
Scientific
Participants
Official Address Other Information
2Pedro AlzariUnité de Biochimie Structurale
Institut Pasteur
25-28, rue du Docteur Roux
FR-75724 Paris Cedex 15
France
Tel: +33 1 45 68 86 07
Fax: +33 1 45 68 86 04
E-mail: alzari@pasteur.fr
3Brigitte GicquelUnité de Génétique Mycobactérienne, Institut Pasteur
25-28, rue du Docteur Roux
FR-75724 Paris Cedex 15
France
Tel: +33 1 45 68 88 28
Fax: +33 1 45 68 88 43
E-mail: bgicquel@pasteur.fr
4Stefan H. E. KaufmannMax-Planck Institute for Infection Biology
Monbijoustrasse 2
DE-10117 Berlin
Germany
Tel: +49 30 28 460502
Fax: +49 30 28 460501
E-mail: kaufmann@mpiib-berlin.mpg.de
5Ida RosenkrandsStatens Seruminstitut
Bacterial Vaccine Department
5 Artillerivej
DK-2300 Copenhagen S
Denmark
Tel: +45 32 683721
Fax: +45 32 683035
E-mail: idr@ssi.dk
6Ute MöllmannHans-Knöll-Institut für Naturstoff-Forschung
Beutenbergstr. 11
DE-07745 Jena
Germany
Tel: +49 3641 656656
Fax +49 3641 656652
E-mail: moellman@pmail.hki-jena.de
7Andrew MunroUniversity of Leicester
University Road
UK-LE1 7RH Leicester
United Kingdom
Tel: +44 116 252 3464
Fax: +44 116 252 3369
E-mail: awm9@le.ac.uk
8Michael ArandInstitute of Toxicology
University of Mainz
Obere Zahlbacher Str. 67
DE-55131 Mainz
Germany
Tel: +49 6131 393 4376
Fax: +49 6131 230506
E-mail: arand@mail.uni-mainz.de
9Kai JohnssonInstitute of Organic Chemistry
University of Lausanne
CH-1015 Lausanne
Switzerland
Tel: +41 21 692 3956
Fax: +41 21 692 3965
E-mail: kai.johnsson@ico.unil.ch
10Nicholas KeepDepartment of Crystallography,
Birkbeck College, University of London
Malet Street
UK-WC1E 7HX London
United Kingdom
Tel: +44 20 7631 6852
Fax: +44 20 7631 6803
E-mail: n.keep@bbk.ac.uk
11Keith S WilsonStructural Biology Laboratory
Department of Chemistry
University of York
Heslington
UK-YO1 5DD York
United Kingdom
Tel: +44 1904 432519
Fax: +44 1904 410519
E-mail: keith@yorvic.york.ac.uk
12Yves BourneAFMB, CNRS UPR9039
31, Chemin Joseph Aiguier
FR-13402 Marseille Cedex 20
France
Tel: +33 4 91 82 86 24
Fax: +33 4 91 82 86 21
E-mail: vantil@esil.univ-mrs.fr
13Alwyn JonesDepartment of Cell and Molecular Biology
Biomedical Centre
Uppsala University
Box 596
SE-751 Uppsala
Sweden
Tel: +46 18 471 4982
Fax: +46 18 536 971
E-mail: alwyn@xray.bmc.uu.se

 
 
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