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Content archived on 2024-05-29

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


TB is one of the most deadly infectious disease in the world. The high rates of patient non-compliance lead to more than three 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 side-effects of treatment, and materially decrease the costs of treatment.

We have made four scientific breakthroughs which indicate that it is feasible to develop such a drug:
1. 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. We have obtained information on ligands which shall be directly submitted to lead optimization pipeline.
2. Our work has shown that persistent M. tuberculosis is metabolically active, and thus should be susceptible to specific chemotherapy, albeit different from current antibiotics.
3. 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.
4. We have identified unique compounds which kill M.tuberculosis including Rifampicin resistant strains. In the current project, we plan to apply our 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 are effective against multi-drug resistant TB.

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