Keywords: Mycobacterium tuberculosis, NO stress, truncated hemoglobins, structure-function relationships, drug design
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.
The basic assumption of this project is that the nitrosative stress resistance of M. tuberculosis might be largely diminished by affecting the activity of the trHbN, thus contributing to decreasing the capability of the microorganism to rest in latency in the infected organism. The hypothetical NO detoxification role makes trHbN a potential therapeutic target, as the design of effectors that might affect the efficiency of the NO detoxification should be valuable to weaken the resistance of the microorganism in the framework of a multi-target therapeutic strategy.
Accordingly, our objectives are:
The project is also expected to validate the truncated hemoglobin N as a suitable target in TB and to calibrate the development of new therapeutic strategies against the disease. To this end, the specific results that should be achieved are:
The results obtained in this project should be valuable in developing new therapeutic strategies against TB.
F. J. Luque
University of Barcelona
|Official Address||Other Information|
|1||Kanak Dikshit||Institute of Microbial Technology
|2||Dario Estrin||University of Buenos Aires
|3||Ignacio Fita||Institute of Molecular Biology of Barcelona
|4||Robert Poole||University of Sheffield