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Characterization and exploitation of the mycothiol redox system of Mycobacterium tuberculosis (IWT481)

Tuberculosis (TB), once referred to as the ''white death'', is a debilitating human disease caused by Mycobacterium tuberculosis (Mtb). Every 20 seconds a person dies from TB, which sums up to over 2 million deaths each year. Mtb lives and survives in macrophages, which generate antimicrobial radicals such as reactive oxygen species and reactive nitrogen species. As a successful intracellular pathogen, Mtb has evolved with powerful defense strategies to detoxify superoxide and nitric oxide in order to maintain its viability and to achieve long-term persistence in human organs. The mechanisms by which Mtb detoxifies ROS and RNS are of particular interest because this knowledge will help us to understand the organism's pathogenesis and its ability to persist, which in turn leads to latent infection.
My main aim is to reveal new redox pathways involved in the oxidative stress defense of the bacterial pathogen Mycobacterium tuberculosis during persistence in human macrophages. The main focus will be on revealing the interaction networks unique for Mtb, and not present in humans. We will focus in this proposal on the mycothiol (MSH)/mycoredoxin (Mrx) redox regulation pathways not present in humans and only found in Actinobacteria. Therefore, we would like to achieve a robust understanding of the functional versatility of the MSH/Mrx redox pathways in the survival of Mtb under oxidative stress. We will profile Mtb under oxidative stress conditions, map its sulfenome, identify the interacting proteins of the MSH/Mrx pathways, biochemical and structural characterize the Mrxs with their most promising interacting proteins, and reconstitute the electron transfer pathways in vitro. We strongly believe that these findings will give us a completely new and groundbreaking view on the survival of Mtb under oxidative stress conditions, and on top of that the reconstituted electron transfer pathways will form a powerful new toolbox for the screening of anti-tuberculosis compounds.
Date:1 Jan 2010  →  31 Dec 2013
Keywords:Holography, Non-Linear Optics, Photonics, Optival Instrumentation, Optical Computing, Semiconductor Technology, Optical Switches And Modulators, Optical Fibre Sensors, Optical Measurements, Optical Materials, Optical Interconnects, Vcsels, Optical Instrumentation, Micro-Optics, Opto-Electronic Devices, Plastic Photonics
Disciplines:Physical sciences, Electrical and electronic engineering, Mathematical sciences