Keywords: Tuberculosis; drug targets; 3-D structure; lead compounds; HT-screening; drug resistance; new drugs
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:
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.
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.
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.
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.
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.
|Official Address||Other Information|
|2 || ||A.F.R.M. Coates |
Department of Medical Microbiology
St George’s Hospital Medical School
UK-SW17 0RE London
|Tel: +44 20 8725 5725 |
Fax: +44 20 8672 0234
|3 ||Gunter Schneider ||Department of Medical Biochemistry and Biophysics |
Scheels väg 2
SE-171 77 Stockholm
|Tel: +46 8 52487675 |
Fax: +46 8 327626
|4 ||Marcus Kalesse ||Institute of Organic Chemistry |
University of Hanover
|Tel: +49 511 762 4688 |
Fax: +49 511 762 3011
|5 ||Paul Driscoll ||Department of Biochemistry and Molecular Biology |
University College London
UK-WC1E 6BT London
|Tel: +44 20 7679 7035 |
Fax: +44 20 7679 7193
|6 ||Hans-Jürgen Hecht ||GBF – German National Centre for |
Mascheroder Weg 1
|Tel: +49 531 6181 369 |