Essential acyl-CoA carboxylases as targets for the identification on new antimycobacterial hits

GRAMAJO HUGO

Congreso; SLAM TB; 2016

Mycobacterium tuberculosis, continues to be a major health problem worldwide. Mycolic acids, one of the most important lipids of the outer membrane of mycobacteria, have been largely associated with bacterial virulence and antibiotic resistance and its biosynthesis pathway is one of the main targets for TB treatment. Biosynthesis of mycolic acids involves two structural distinct fatty acid synthase systems, FAS-I capable of de novo synthesis of long- and very long-chain fatty acids, and FAS-II, responsible for their elongation to synthesize the meromycolic acids. These two systems should work in a finely coordinate manner to keep lipid homeostasis tightly regulated. The main purpose of our studies is to understand how mycobacteria exert this exquisite control over the biosynthesis of their membrane lipids and for that we identified and characterized two transcriptional regulators, FasR and MabR, involved in the regulatory network that controls fatty acid and mycolic acid biosynthesis, respectively. Here, I present the biochemical characterization of these regulatory proteins and discuss their physiological role through the detailed characterization of mutants constructed in Mycobacterium smegmatis and in M. tuberculosis. Finally, I will discuss the possibility of using these key components of the biosynthetic and regulatory network involved in mycolic acid biosynthesis as targets for the identification of new anti-mycobacterium compounds.