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

HUGO GRAMAJO

Congreso; VIII SLAMTB; 2016

Mycolic acids and multi-methyl branched fatty acids are key constituents of the cell envelope and cell wall of M. tuberculosis. These unusually long fatty acids are important for the TB defense and virulence mechanisms. Inhibitors of mycolic acid biosynthesis include antibiotics such as isoniazid. Acyl-CoA Carboxylases (ACCase) catalyze the committing step of acyl-CoAs to the biosynthesis of these unique cell wall lipids by the carboxylation of acyl-CoAs to form the basic building blocks for subsequent production of mycolic acids and mycocerosic acids. Our goal is to (1) Define the roles of multiple ACCases (1 to 6) found in M. tuberculosis. (2) Solve the crystal structure of TB ACCases, that will provide a molecular basis for their unique substrate specificities towards different acyl-CoAs. (3) Design ACCase inhibitors that will shut down cell wall lipid biosynthesis and kill the pathogen. We have identified, cloned and crystallized AccD4, AccD5 and AccD6 of M. tuberculosis, and solved the crystal structure of AccD5 and AccD6. We have defined the biological roles of AccD4-6 as the provider of extender units for mycolic acid, methyl-branched fatty acids, and straight-chain fatty acids, respectively. Using the UC Irvine ChemDB, as well as a combination of structure-based drug design softwares, we have identified potent inhibitors of AccD4-6 that stop the pathogen growth. The structure-activity relationship of these lead compounds will be presented and their potential as future tuberculosis therapeutics will be evaluated.