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Unraveling the molecular mechanism of nitrosative stress resistance in tuberculosis

Unraveling the molecular mechanism of nitrosative stress resistance in tuberculosis

Objective

Tuberculosis is today amongst the major worldwide health threats. Treatment failure is unfortunately becoming more usual, especially in countries lacking the long and costly treatment adapted to patients. Thus, tuberculosis causes 2 million deaths every year and latently persists in over 1 billion individuals worldwide. Current treatments are challenged by multidrug resistant strains, drug side effects, and co-infections. Therefore, identification of potent, safety antimycobacterial agents is mandatory. However, the success of this strategy is largely determined by the detailed knowledge of their mechanism of action, which in turn depends on the validation of suitable biological targets. This project pursues the definition of new, complementary therapeutic approaches by identifying the molecular basis of the nitrosative stress resistance of M. tuberculosis. Our working hypothesis is that a decrease in the NO resistance of the microorganism should reduce significantly 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. Accordingly, our objectives are i) to unravel the molecular mechanism underlying the NO dioxygenase activity of M. tuberculosis trHbN, ii) to establish the structure-function relationships in trHbN and trHbO from M. tuberculosis, and iii) to identify the reductase protein system that helps trHbN to restore the ferrous state required to initiate the NO detoxification cycle. The outcome of the project should provide a firm basis to assess the viability of trHbN as a therapeutic target, and set up the background to exploit this knowledge in the design of innovative therapeutic strategies to fight the disease.
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Coordinator

UNIVERSITAT DE BARCELONA

Address

Gran Via De Les Corts Catalanes 585
08007 Barcelona

Spain

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 293 798

Administrative Contact

F. Javier Luque (Prof.)

Participants (4)

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COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

India

EU Contribution

€ 54 000

UNIVERSIDAD DE BUENOS AIRES

Argentina

EU Contribution

€ 125 750

AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS

Spain

EU Contribution

€ 285 216

THE UNIVERSITY OF SHEFFIELD

United Kingdom

EU Contribution

€ 404 500

Project information

Grant agreement ID: 223335

Status

Closed project

  • Start date

    1 October 2008

  • End date

    31 March 2012

Funded under:

FP7-HEALTH

  • Overall budget:

    € 1 540 956,40

  • EU contribution

    € 1 163 264

Coordinated by:

UNIVERSITAT DE BARCELONA

Spain