Thesis presented October 10, 2024

Abstract:
Mycobacterium tuberculosis (Mtb), the causative microorganism of Tuberculosis (TB), remains one of the most successful pathogens and the leading cause of death from a single pathogen in the world following Covid-19. Mtb is estimated to infect a quarter of the world population resulting in a mortality rate of 1.5 millions per year. The escalating emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) strains to actual antitubercular treatments explains the urgent need to develop new antitubercular drugs acting on novel targets. An attractive new target could probably be the Iron-Sulfur clusters [Fe-S]. These are small inorganic cofactors consisting of iron (Fe²⁺/Fe³⁺) and sulfides in different oxidation forms [2Fe-2S], [3Fe-3S] and [4Fe-4S], that are essential in various biological processes (e.g., DNA repair, respiration, photosynthesis, cofactor biosynthesis). Five machineries involved in Fe-S biogenesis have been identified in bacteria: the NIF, ISC, SUF, SMS and MIS systems. Interestingly, Mtb contains only the SUF system as Fe-S assembly machinery. SUF system is essential for in vitro growth of Mtb under normal and stress conditions and recently proved to be a point of vulnerability in Mtb. Our research objective is to characterize the SUF proteins and to find inhibitors of the SUF machinery as potential new antitubercular agents.

Keywords:
Tuberculosis ; Iron-Sulfur clusters; SUF machinery; protein-protein interactions; Mycobacterium tuberculosis; Anti-tubercular