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TB prevention cluster
TUBERCULOSIS
Framework programme: 5
Project number:
QLK2-CT-2000-01761
EC contribution: € 2 000 000
Duration: 48 months
Type: RS
Starting date: 1 December 2000
Graphic element New Strategies for Treatment and Prevention of Mycobacterial Diseases
Keywords: Tuberculosis; drug development; treatment; prevention; drug resistance; molecular genetics; crystallography; biochemistry

Summary:

The overall objective of the cluster project is to establish a European framework to develop new strategies for the treatment of mycobacterial diseases. The project will study the mycobacterial cell wall structure to overcome the permeability barrier mediating innate drug resistance and characterise mycobacterial targets for future drug design. Integration of these activities, with the participation of leading research groups in Europe, is essential for completing the goal of developing novel approaches for control of infections with Mycobacterium tuberculosis.

Problem:

Tuberculosis, the white plague of former times, represents a major health problem worldwide. It is still the single largest cause of death amongst all bacterial infections: 3 million people die each year of tuberculosis, and one third of the world’s population is being infected with Mycobacterium tuberculosis, the causative bacterial agent. A particularly threatening development has been the emergence of strains of M. tuberculosi,s which are resistant to all of the front-line antituberculous drugs. There is, therefore, an urgent need to tackle the problem of treatment with infections with M. tuberculosis, both with an understanding of drug resistant mechanisms and working towards a development of new drugs with antimycobacterial activity.

One of the major problems in developing antibiotics with antimycobacterial activity is the unusual mycobacterial cell wall with an intrinsically low permeability, making these microorganisms resistant to most commonly used antibacterial agents. This permeability barrier serves as a rate-limiting step in drug uptake and is controlled by properties of the cell envelope.

Many of the existing antituberculous drugs target the synthesis of the mycobacterial cell wall, and the unusual structure of the cell wall makes this a particularly fertile area for developing new antituberculosis agents. More recently, the availability of the M. tuberculosis genome sequence has provided unprecedented insights into physiological processes, which may point toward completely novel drug targets.

Aims:

Rapid progress in the fields of biochemistry and mycobacterial genetics provides exciting new opportunities for developing new strategies for treatment of mycobacterial diseases. The TB prevention cluster provides a multidisciplinary European approach, including the areas of biochemistry, genetics, crystallography, lipid chemistry and microbiology, and is based on an integrated goal-orientated strategy. The cluster combines two areas of fundamental importance to tackle the problem of tuberculosis: (i) cell wall structure, permeability and innate drug resistance, (ii) novel drug targets.

The general aims of the areas of work are:

  1. to understand the architecture of the M. tuberculosis cell wall to overcome the inefficient transport of many antibiotics across the mycobacterial cell wall, and to investigate the involvement of cellular transport and permeability in innate and acquired drug resistance
  2. to identify, produce and characterise novel drug targets, to carry out structural analysis as a requisite for developing new inhibitors, and to prioritise these novel drug targets to take them forward for collaborations within a commercial environment where there is expertise in synthetic and combinatorial chemistry and structure-activity-based drug design.

Expected results:

  • Identification of novel potential and promising candidate enzymes involved in the synthesis of the mycobacterial cell wall as a drug target.
  • Characterisation of mycobacterial structures for future drug design.
  • Role of membrane components in drug resistance.
  • Strategies to overcome innate mycobacterial drug resistance.

Potential applications:

Strategies fuelling into optimal use of existing antimycobacterial agents, the means to overcome innate mycobacterial drug resistance and the identification of novel targets for anti-infective drugs will have a major impact on tuberculosis control.

Coordinator:

Erik C. Böttger
Institut für Medizinische Mikrobiologie
Universität Zürich
Gloriastrasse 30/32
8028 Zurich
Switzerland
Tel: +41 1 634 2660
Fax: +41 1 634 4906
E-mail: boettger@immv.unizh.ch

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Mats AnderssonDepartment of Medical Biochemistry and Biophysics
Karolinska Institutet
SE-17177 Stockholm
Sweden
Tel: +46 8 728 7699
Fax: +46 8 337 462
E-mail: mats.andersson@mbb.ki.se
3Alexander AptLaboratory for Immunogenetics
Central Institute for Tuberculosis
Yauza Alley 2
RU-107564 Moscow
Russia
Tel: +7 095 268 7810
Fax: +7 095 144 5618
E-mail: asapt@aha.ru
4M. Jo ColstonNational Institute for Medical Research
Division of Mycobacterial Research
The Ridgeway Mill Hill
UK-NW7 1AA London
United Kingdom
5Bruno CurtiDipartimento di Fisiologia e Biochimica Generali
Università degli Studi di Milano
IT-Milan
Italy
Tel: +39 02 7064 4504
Fax: +39 02 2362 451
E-mail: brunocurti@unimi.it
6Mamadou DaffeInstitut de Pharmacologie et de Biologie Structurale
CNRS
205, Route de Narbonne
FR-31077 Toulouse
France
Tel: +33 5 61 17 55 69
Fax: +33 5 61 17 59 93
E-mail: daffe@ipbs.fr
7Brigitte GicquelUnité de Génétique Mycobactérienne
Institut Pasteur
25, Rue du 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
8Giulio MagniInstituto de Biochimica
Facultà di Medicina e Chirurgia
Università di Ancona
Via Ranieri
IT-60100 Ancona
Italy
Tel: +39 071 2204 678
Fax: +39 071 2802 117
E-mail: magnig@popcsi.unian.it
9Carlos MartínFacultad de Medicina
Dpto Microbiologia y Salud Publica
Universidad de Zaragoza
C/Domingo Miral s/n
ES-50009 Zaragoza
Spain
Tel: +34 9 7676 1759
Fax: +34 9 7676 1664
E-mail: carlos@posta.unizar.es
10John Joe McFaddenMolecular Microbiology Group
School of Biological Sciences
University of Surrey
UK-GU2 5XH Guildford
United Kingdom
Tel: +44 483 300800 / 2671
Fax: +44 483 300374
E-mail: j.mcfadden@surrey.ac.uk
11Michael NiederweisLehrstuhl für Mikrobiologie
Universität Erlangen
Staudtstr. 5
DE-91058 Erlangen
Germany
Tel: +49 9131 852 8802
Fax: +49 9131 852 8082
E-mail: mnieder@biologie.uni-erlangen.de
12Giovanna RiccardiDipartimento di Biologia Sperimentale
Ambiente ed Applicata
Università di Genova
Viale Benedetto XV, no. 5
IT-16126 Genova
Italy
Tel: +39 010 353 8252
Fax: +39 010 353 8267
E-mail: riccardi@unige.it
13Menico RizziUniversità di Piemonte Orientale “A. Avogadro”
Viale Ferrucci 33
IT-28100 Novara
Italy
Tel: +39 0321 657632
Fax: +39 0321 657641
E-mail: rizzi@pharm.unipmn.it
14Edda de RossiDipartimento di Genetica e Microbiologia
Università degli Studi di Pavia
Via Abbiategrasso 207
IT-27100 Pavia
Italy
Tel: +39 0382 505575
Fax: +39 0382 528496
E-mail: derossi@ipvgen.unipv.it
15Douglas YoungWright Fleming Institute
Department of Medical Microbiology
St. Mary’s Hospital Medical School
Norfolk Place
UK-W2 1PG London
United Kingdom
Tel: +44 171 594 39 62
Fax: +44 171 262 62 99
E-mail: d.young@ic.ac.uk

 
 
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