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:

Partners:

Nº	Principal Scientific Participants	Official Address	Other Information
2	Mats Andersson	Department 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
3	Alexander Apt	Laboratory 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
4	M. Jo Colston	National Institute for Medical Research Division of Mycobacterial Research The Ridgeway Mill Hill UK-NW7 1AA London United Kingdom
5	Bruno Curti	Dipartimento 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
6	Mamadou Daffe	Institut 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
7	Brigitte Gicquel	Unité 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
8	Giulio Magni	Instituto 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
9	Carlos Martín	Facultad 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
10	John Joe McFadden	Molecular 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
11	Michael Niederweis	Lehrstuhl 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
12	Giovanna Riccardi	Dipartimento 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
13	Menico Rizzi	Università 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
14	Edda de Rossi	Dipartimento 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
15	Douglas Young	Wright 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