DISCOVERY OF NOVEL INHIBITORS OF THE MYCOBACTERIAL CELL WALL

Tuberculosis remains a major threat in the world; in 2012, 8.6 million new TB cases were found. After the human immunodeficiency virus (HIV), TB has been considered as one of the most infectious diseases in history and the second leading cause of death. Effective drugs treatments are known and have been used since 1960. New TB drugs have been tested in clinical trials. However, the appearance of multidrug resistant strains has urged the research for finding new therapeutic agents to cure tuberculosis. Among the different enzymes involved in the formation of the mycobacterial cell wall, UDP-Galactopyranose mutase (UGM) was identified as a new target. Indeed, this enzyme allows a peculiar reaction: the contraction of the cycle of UDP-Galp into UDP-Galf. This thesis was based on the identification of novel potential inhibitors of UGM in order to understand the mechanism of this enzyme. The enzymatic studies were performed on two different categories of molecules: UDP-F4-Galactose and natural products. In the first part of this project, we synthesized polyfluorinated sugars, UDP-F4-Galactose, as analogues of the natural substrate UDP-Galactofuranose. Thus, four fluorine atoms were introduced at 2 and 3 positions of the galactose. Then, biochemical assays of these molecules were carried out on UGM. The inhibition study allowed us to determine the binding affinity present between the UDP-F4-Galactose and the enzyme. The second part reported the screening of a small library of natural compounds which lead to identify new potential inhibitors of UGM. Biochemical assays and molecular modeling studies have been performed on these molecules to better understand the interactions between these compounds and UGM within the active site.