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NEWTBDRUGS
TUBERCULOSIS
Framework programme: 6
Call: 3
Project number:
LSHP-CT-2005-018729
EC contribution: € 1 800 000
Duration: 36 months
Type: STREP
Starting date: 1 September 2005
Graphic element New Drugs for Persistent Tuberculosis: Exploitation of 3-D Structure of Novel Targets, Lead Optimisation and Functional In-Vivo Evaluation
Keywords: Tuberculosis; drug targets; 3-D structure; lead compounds; HT-screening; drug resistance; new drugs

Summary:

TB is one of the most deadly infectious diseases in the world. The high rates of patient non-compliance lead to more than 3 million deaths per year, as well as to the creation of chronic, infectious, drug-resistant TB strains, against which almost all existing antibiotics are ineffective or prohibitively toxic. A short course of chemotherapy (two months or less) would significantly increase patient compliance, substantially reduce the rate of emergence of antibiotic resistance, decrease the side effects of treatment and materially decrease the costs of treatment. Four scientific breakthroughs have been made by this study, which indicate that it is feasible to develop such a drug:

  1. As part of a research project supported by the EC, we have recently solved the 3-D structure of several persistence related drug targets of M. tuberculosis. Information on ligands has been obtained which shall be directly submitted to lead optimisation pipeline.
  2. Our work has shown that persistent M. tuberculosis is metabolically active, and thus should be susceptible to specific chemotherapy, albeit different from current antibiotics.
  3. New assays have been developed for screening drugs which kill persistent M. tuberculosis. These assays can distinguish between drugs such as isoniazid, which have little action against persisters, and compounds, which are known to have some anti-persister activity such as pyrazinamide.
  4. Unique compounds have been identified by this study, which kill M. tuberculosis including Rifampicin resistant strains.

In the current project, the team plans to apply its integrated strategy to the drug development pipeline by structural analysis of novel targets, virtual and real screening-based identification of leads, new organic synthetic chemistry and functional evaluation in mice. The outcome of this project is expected to lead to new drugs which will shorten the duration of TB treatment, will improve the treatment of latent TB infection and will be effective against multidrug resistant TB.

Background:

The key problem arising in tuberculosis treatment is the six to eight month-long treatment duration which very often leads to non-compliance. Patients frequently get better quickly on an intense course of antibiotic chemotherapy and therefore stop taking the drugs before the infection is eliminated. MDR-TB has become a major health problem, not only in developing countries but also in neighbouring countries of the European Community. In the face of the HIV/AIDS epidemic, new ‘sterilising’ drugs with shorter regimens are needed that can significantly increase patient compliance, substantially reduce the rate of emergence of antibiotic resistance, materially decrease the costs of treatment and prevent progression from latent infection to active disease. New strategies are urgently needed for combating the problems of TB treatment.

Aim:

In the current project, the aim is to apply our integrated strategy of drug development by structural analysis of novel targets, virtual and real screening-based identification of leads, new organic synthetic chemistry and functional evaluation of best hits in in-vivo animal models.

Expected results:

The outcome of this project is expected to lead to new drugs which will shorten the duration of TB treatment, will improve the treatment of latent TB infection and will be effective against multidrug resistant TB.

Potential applications:

It is anticipated that at least one of the leads identified and developed in this project will enter clinical trials in humans for treating persistent TB. This will be done in cooperation with pharmaceutical companies which are engaged in manufacturing the current TB drugs. Similarly, at least one novel lead will enter clinical trial for treating drug resistant TB.

Coordinator:

Mahavir Singh
LIONEX Diagnostics and Therapeutics GmbH
Mascheroder Weg 1 b
38124 Braunschweig

Germany
Tel: +49 531 2601266
Fax: +49 531 260 11 59
E-mail: info@lionex.de
Website: http://www.lionex.de

Partners:

Principal
Scientific
Participants
Official Address Other Information
2

A.F.R.M. Coates
Department of Medical Microbiology
St George’s Hospital Medical School
Cranmer Terrace
UK-SW17 0RE London
United Kingdom
Tel: +44 20 8725 5725
Fax: +44 20 8672 0234
E-mail: acoates@sghms.ac.uk
Website: http://www.sgul.ac.uk/
3
Gunter Schneider
Department of Medical Biochemistry and Biophysics
Karolinska Institutet
Scheels väg 2
SE-171 77 Stockholm
Sweden
Tel: +46 8 52487675
Fax: +46 8 327626
E-mail: gunter.schneider@mbb.ki.se
Website: http://www.ki.se
4
Marcus Kalesse
Institute of Organic Chemistry
University of Hanover
Schneiderberg 1B
DE-30167 Hanover
Germany
Tel: +49 511 762 4688
Fax: +49 511 762 3011
E-mail: Markus.Kalesse@oci.uni-hannover.de
Website: http://www.uni-hannover.de
5
Paul Driscoll
Department of Biochemistry and Molecular Biology
University College London
Gower Street
UK-WC1E 6BT London
United Kingdom
Tel: +44 20 7679 7035
Fax: +44 20 7679 7193
E-mail: p.driscoll@ucl.ac.uk
Website: www.biochem.ucl.ac.uk/research/driscoll/driscoll.htm
6
Hans-Jürgen Hecht
GBF – German National Centre for
Biotechnology
Mascheroder Weg 1
DE-38124 Braunschweig
Germany
Tel: +49 531 6181 369
E-mail: hjh@gbf.de
Website: http://www.gbf.de

 
 
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