Summary:

The primary objective of this project is to identify suitable drug targets and to discover lead compounds suitable for development into new drugs active against tuberculosis.
The plan of action is to:

1. Express and purify each protein being targeted using available expression systems;
   
2. Determine the structure of each protein by X-ray crystallography;
   
3. Develop biochemical assays suitable for adaptation to high-throughput screening (HTS);
   
4. Screen for and identify inhibitors for each protein where a suitable assay has been developed;
   
5. Assess the effectiveness of the best inhibitors identified against Mycobacterium tuberculosis in vitro, and;
   
6. Optimise lead compounds by medicinal chemistry.

Background:

Tuberculosis (TB) causes more deaths worldwide than almost any other infectious disease, with nearly two million deaths per year and devastating impact on developing countries. More effective means of medical intervention are required, both to reduce the number of deaths from tuberculosis and to allow for more effective treatment of drug-resistant infections.

Aim:

The TB-DRUG project aims to discover novel compounds against Mycobacterium tuberculosis which can be developed into products that can alleviate the global burden of TB, by carefully selecting proteins to be taken into the drug discovery process as novel targets. In anticipation of the significant attrition rate of the drug discovery process, it is suggested that the different targets are included at the earliest stages of drug development, followed by a more focused approach on the most promising candidates in the later stages. The project will be carefully managed by taking advantage of industrial knowledge in planning and management. As a minimal outcome of this consortium the aim is to identify 2-3 attractive leads to be taken forward into a preclinical drug development phase.

Expected results:

It is expected that the proposed work will result in:

1. Expression and purification of each protein being targeted
2. Structure determination of each protein purified by X-ray crystallography
3. Development of biochemical assays suitable for adaptation to HTS for each target purified
4. Screening for and identification of inhibitors for each protein for which a suitable assay has been developed
5. Assessment of the effectiveness of the best inhibitors identified against live M. tuberculosis in-vitro
6. Optimisation of lead compounds by medicinal chemistry.

Potential applications:

TB patients in parts of Eastern Europe and Central Asia have a significant risk of acquiring multidrug-resistant TB (MDR-TB). TB incidence rates also continue to rise at an alarming rate in African countries with high HIV prevalence. This rise of MDR-TB and increased susceptibility to TB caused by co-infection with HIV is driving the worldwide TB epidemic and is likely to worsen in the years to come. The discovery of novel antitubercular drugs not only promises to benefit people in the eastern European, Asian and African countries who suffer most from TB, but also to fight the spread of MDR-TB that could fuel a TB epidemic in all of Europe.

By bringing together scientists from many different disciplines and by connecting academics with industry research, TB-DRUG establishes an integrated drug discovery and development process. The range of complementary expertise available within the proposed Project, together with a state-of-the-art discovery technology, facilitates the entire process of preclinical drug discovery. The TB-DRUG Consortium strives to have a significant impact in the area of TB drug development and to contribute to the education of young scientists by offering exceptional teaching and training opportunities for post-doctoral fellows and PhD students.

Coordinator:

Partners:

Nº	Principal Scientific Participants	Official Address	Other Information
2	Mamadou Daffé	Institut de Pharmacologie et Biologie Structurale Université Paul Sabatier CNRS UMR 5089 205 Route de Narbonne F-31077 Toulouse Cedex France	Tel: +33 561 175 569 Fax: +33 561 175 580 Email: mamadou.daffe@ipbs.fr Website: www.ipbs.fr
3	Menico Rizzi	Dipartimento di Scienze Chimiche Alimentari, Farmaceutiche e Farmacologiche (DiSCAFF) University of Piemonte Orientale ‘Amedeo Avogadro’, Via Bovio 6 I-28100 Novara Italy	Tel: +39 0321 375 812 Fax: +39 0321 375 821 Email: rizzi@pharm.unipmn.it Website: www.discaff.unipmn.it
4	Peter Sander	Institut für Medizinische Mikrobiologie University of Zurich, Gloriastrasse 30/32, CH-8006 Zurich Switzerland	Tel: +41 44 634 2684 Fax: +41 44 634 4906 Email: psander@immv.unizh.ch Website: www.imm.unizh.ch
5	Andrea F. Degen Iseli	R&D Management GmbH Stockerstrasse 37 CH-8002 Zurich Switzerland	Tel: +41 44 748 39 74 Fax: +41 44 748 41 74 Email:ad@researchmanagement.ch Website: www.researchmanagement.ch