Towards New Tuberculosis Therapeutics Against Acyl-CoA Carboxylase (ACCase) of Mycobacterium tuberculosis.

LIN, T., KURTH, D., SHILLITO, B., GAGO, G., FISCHBACH, M., WALSH, C., SWAMIDASS, J., BALDI, P., GRAMAJO, H. AND TSAI, S

Oxford, Inglaterra

Simposio; Gordon Research Conference: “Tuberculosis Drug Development”.; 2007

Mycolic acids and multimethyl-branched fatty acids are found uniquely in the cell envelope of Mycobacterium tuberculosis and are essential for its survival, virulence, and antibiotic resistance. Acyl-CoA carboxylases (ACCases) commit acyl-CoAs to the biosynthesis of these unique fatty acids. The roles of the six ACCase carboxyltransferase domains, AccD1–6, are not well defined, but previous studies indicate that their disruption leads to pathogen death. We have determined the crystal structures of AccD5 and AccD6, whose sequence, structure, and active site are highly conserved. Both crystal structures and kinetic assay indicate that AccD5 and AccD6 accepts both acetyl- and propionyl-CoAs, with likely biological roles of  providing the building block for the biosynthesis of mycolic acids an multimethyl-branched fatty acids. Extensive in silico screening of compounds from National Cancer Institute and UC Irvine’s ChemDB database resulted in the identification of potent inhibitors with sub-micromolar IC50 and MIC. Our results pave the way toward understanding the biological roles of ACCases, in addition to providing a new target for structure-based development of antituberculosis therapeutics