Regulatory network of lipid biosynthesis in mycobacteria: possible new targets for drug Discovery.

SONIA S MONDINO; VALENTINA SALZMAN; GABRIELA GAGO; HUGO C GRAMAJO

Luca

Conferencia; Gordon Research Conferences 2011 Tuberculosis Drug Development; 2011

Gordon Research Conferences

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 and FAS-II. 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 find out the key components of the regulatory network that control fatty acid and mycolic acid biosynthesis at the transcriptional level. Here, we present the in vivo an in vitro characterization of MabR, the transcriptional regulator of the fasII operon, and of FasR, a new regulatory protein that specifically binds pfas to regulate the de novo fatty acid biosynthesis. We also present evidences that a long-chain acyl-CoA is the effector molecule that co-ordinates the expression of the two FAS systems at the transcriptional level. Finally, we discuss the possibility of using these regulatory proteins as new targets for the development of new strategies to control TB.