NEWTBDRUGS

New drugs for persistent tuberculosis: exploitation of 3D structure of novel targets, lead optimisation and functional in vivo evaluation

EC contribution: : € 1.800.000
Duration: : 36 months
Starting date: : 01/09/2005
Funding scheme: : Specific Targeted Research Project
Keywords: : tuberculosis, drug targets, 3D structure, lead compounds, HT-screening, drug resistance, new drugs
Contract/Grant agreement number: : LSHP-CT-2005-018729
Project web-site: : -

Background:

Tuberculosis (TB) is one of the most deadly infectious diseases in the world. The high rates of patient non-compliance lead not only to more than 3 million deaths per year, but also 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 the NEWTBDRUGS project would lead to new drugs that would shorten the duration of TB treatment, improve latent TB infection treatment and be effective against multidrug-resistant TB (MDR-TB).

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Problem:

The key problem in TB treatment is the six- to eight-month-long treatment duration, which 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:

The NEWTBDRUGS consortium aimed to apply their 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 and obtained 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.
We expect to solve the 3-D structure of three drug targets (NirA, CysK, ALD) and to confirm by k.o. mutant construction that these are valid drug targets.

We expect to verify whether nirA is really a a nitrite reductase.

By In-Silico screening several hits are expected to be identified which shall be organically synthesized or purchased and tested against the drug targets by assaying the enzymes . For this new enzyme assays are expected to be developed which can be used in HT-format.

Detailed SAR by NMR is expected to add greatly to the identification of hits against targets.

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:

Dr. Mahavir Singh
LIONEX Diagnostics and Therapeutics GmbH
Inhoffenstrasse 7
38124 Braunschweig, Germany
Tel. +49 5312601266
Fax +49 5312601159
E-mail: info@lionex.de

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