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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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