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NOstress


Unraveling the molecular mechanism of nitrosative stress resistance in tuberculosis
 
 
Framework programme:
 7
Contract/Grant agreement number:
223335
EC contribution:
1,160,000 €
Duration:
36 months
Funding scheme:
Collaborative project SICA
Starting date:
01/10/2008

Keywords: Mycobacterium tuberculosis, NO stress, truncated hemoglobins, structure-function relationships, drug design

Background

Tuberculosis (TB) is currently causing 2 million deaths every year and latently persists in over 1 billion individuals worldwide. Treatment failure of TB is unfortunately becoming more widespread, especially in countries lacking the means for the long and costly treatment necessary. Current treatments are challenged by multidrug-resistant strains, drug side effects and co-infections. Identification of potent, safe antimycobacterial agents is vital. However, the success of this strategy is largely determined by detailed knowledge of their mechanism of action, which in turn depends on the validation of suitable biological targets required to initiate the nitric oxide (NO) detoxification cycle.

This project pursues the definition of new and complementary therapeutic approaches by identifying the molecular basis of the nitrosative stress resistance of Mycobacterium tuberculosis. NO stress's working hypothesis is that a decrease in the NO resistance of the microorganism should significantly reduce the capability to rest in latency, thus contributing to increase the efficacy of the therapeutic treatment. In this context, understanding of the NO detoxification activity played by M. tuberculosis trHbN is essential.

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