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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.

Field of science

  • /medical and health sciences/clinical medicine/pneumology/tuberculosis
  • /medical and health sciences/basic medicine/pharmacology and pharmacy/drug resistance/multidrug resistance

Call for proposal

FP7-HEALTH-2007-B
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Funding Scheme

CP-SICA - Collaborative project for specific cooperation actions dedicated to international cooperation partner countries (SICA)

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)

COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH
India
EU contribution
€ 54 000
Address
Anusandhan Bhawan, Rafi Marg 2
110001 New Dehli
Activity type
Research Organisations
Administrative Contact
Kanak Dikshit (Dr.)
UNIVERSIDAD DE BUENOS AIRES
Argentina
EU contribution
€ 125 750
Address
Calle Viamonte 430
1053 Buenos Aires
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Dario Ariel Estrin (Prof.)
AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Spain
EU contribution
€ 285 216
Address
Calle Serrano 117
28006 Madrid
Activity type
Research Organisations
Administrative Contact
Mar Sainz Ferrer (Ms.)
THE UNIVERSITY OF SHEFFIELD
United Kingdom
EU contribution
€ 404 500
Address
Firth Court Western Bank
S10 2TN Sheffield
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Ben Williams (Mr.)