Genetic analysis of the decaprenyl-phospho-D-arabinofuranose pathway in Mycobacterium tuberculosis

The tuberculosis (TB) epidemic still represents a major global health problem as it kills more than one million people every year. Africa and Asia are arguably the most affected regions due to the dramatic increase of TB cases in HIV-positive patients and the emergence of drug resistant Mycobacterium tuberculosis strains. One of the features that makes M. tuberculosis difficult to treat is the presence of a thick and highly hydrophobic cell wall that is impermeable to many drugs. The cell wall is composed of mycolic acid, arabinogalactan and peptidoglycan, proteins, free lipids and glycolipids such as the immunogenic lipoarabinomannan and is vital for the survival and virulence of the bacillus. Targeting cell wall biosynthesis represents therefore a topic of outstanding interest, as witnessed by the development of such drugs as isoniazid and ethambutol. In addition, benzothiazinones (BTZ), effective against drug-resistant strains and now in preclinical development, target the production of decaprenyl phospho-D-arabinofuranose (DPA) in the biosynthesis of arabinan. Thus, further investigation on the genetics and biochemistry of cell wall biosynthesis can underpin excellent progress towards the development of new candidate compounds. In this context, my PhD thesis focused on: 1- The biosynthesis of DPA to find new potentially druggable enzymes. 2- The importance of Rv3789 in the biosynthesis of arabinan in M. tuberculosis. 3- The identification of mutations in DprE1 that confer resistance to BTZ. [...]