Abstract
The resurgence of mycobacterial infections reflects the current challenge in the fight against pathogenic microorganisms. Mycobacteria are responsible for severe pulmonary and extra-pulmonary infections, particularly in patients with co-morbidities. Moreover, the high level of antibiotic resistance in these bacterial species leads to numerous therapeutic failures and dead-ends. To bypass them, it is essential to identify new pharmacological targets and active molecules. Enzymes involved in the biosynthesis of mycolic acids, essential components of the mycobacterial wall, represent attractive candidates for the development of new antimycobacterials. Isoniazid, a first-line anti-tuberculosis drug requiring a bioactivation by KatG enzyme, inhibits the enoyl-ACP reductase InhA involved in the elongation of the mycolic chains. However, isoniazid and its analogs sharing the same mode of action, are inoperant against the non-tuberculous mycobacteria, such as M. abscessus or M. fortuitum, due to the incapacity of their KatG protein to bioactive them. In this context, the purpose of my thesis was to demonstrate the interest of targeting the so far untapped mycolic acid synthesis pathway in nontuberculous mycobacteria. Thus, through direct inhibition of the InhA protein in M. abscessus and M. fortuitum, my work demonstrated the robust antibacterial activity of the 4-hydroxy-2-pyridone NITD-916 both in vitro and in various cellular and animal models. Overall, these results are part of a repositioning process in which direct inhibitors of InhA and, more broadly of other enzymes involved in mycolic acid biosynthesis, described earlier in M. tuberculosis, can be transposed to others pathogenic mycobacteria refractory to standard chemotherapy. This work paves the way for future preclinical and clinical studies to expand the therapeutic arsenal available to the physician for the treatment of multi-resistant and persistent mycobacterial infections.