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:
- 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.
- Our work has shown that persistent M. tuberculosis is metabolically active, and thus should be susceptible to specific chemotherapy, albeit different from current antibiotics.
- 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.
- 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
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