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Summary
M_tb

The increasing emergence of multidrug and extensively drug resistant strains of Mycobacterium tuberculosis, the last one being virtually untreatable, urgently demands novel drugs for therapy of tuberculosis. This project has the aim of bringing together a number of research scientists with expertise in a broad range of disciplines, both from Europe and from India, covering the development field from chemistry to in vivo evaluation. The selected targets belong to either the group of targets for which some proof of concept already exists (mycolic acid synthesis and ATP synthase) or to the group of completely new targets that will be validated (thymidylate synthase, acyl-CoA carboxylase, DNA helicase). One alternative strategy to target the host cellular machinery to enhance bacterial killing is, likewise, included. The selected targets are covering fatty acid metabolism, nucleoside synthesis, energy generation, the survival of the microorganism in macrophages and the nucleic acid metabolism. The systems selected include those from which we expect to generate compounds active against replicating Mycobacteria or to obtain compounds targeting latent infection. The application is divided in four scientific work packages, including target validation, the interaction with the host cellular machinery, the design and synthesis of new inhibitors and in vitro and in vivo screening of drug candidates, and one management work package. A considerable part of the drug development and assessment against drug resistant Mycobacterium tuberculosis will be carried out by the Indian partners, one of which is an SME.

Problem

Tuberculosis is a major health problem globally. As reported by the WHO, one third (2 billion) of the world’s population is currently infected with the tuberculosis bacillus. Although tuberculosis was mainly a problem of the third world countries, it has now become more and more a European problem due to immigration and due to the expansion of the European Union to East-European countries. The disease can be treated by chemotherapy. Normally, combinations of three to four first line drugs are given over a period of 4 to 6 months. The protracted course of treatment and the side effects of drugs lead to a high proportion of non-compliance patients. This and other reasons have led to the increasing emergence of multidrug resistant (MDR) strains which need inclusion of second line drugs into the treatment scheme. In several countries of the world, including eastern parts of Europe, high proportions (10-20%) of so-called MDR-TB strains have been noted. More recent is the increasing occurrence of extensively drug resistant (XDR) strains, so-called XDR-TB. The XDR-TB is virtually untreatable and it has been recorded in 38 nations thus far. The increasing incidences of MDR- and XDR-TB urgently demand novel drugs for therapy of tuberculosis. Owing to the low commercial interest in treating TB, it is clearly a disease that should be tackled using financial support of government, European Commission, WHO and philanthropic organizations.

Title: New Approaches to Target Tuberculosis


Acronym: NATT


Contract number: 222965


EC contribution: 2.994.478 €


Duration: 36 months


Starting date: 01/10/2008


Instrument:
Collaborative project