KURTH daniel German
congresos y reuniones científicas
Acyl-CoA carboxylase inhibitors as new antimycobacterial agents
KURTH, D; GAGO, G; DE LA IGLESIA, A; MORBIDONI, HR; TSAI, SC; GRAMAJO, H
Mar del Plata, Argentina
Congreso; XLIII Annual Meeting of the Argentinean Society for Biochemistry and Molecular Biology (SAIB); 2007
Mycolic acids, one the crucial lipids of the sophisticated cell envelope of Mycobacterium tuberculosis, are essential for the survival, virulence, and antibiotic exclusion of this human pathogen. Inhibitors of mycolic acid biosynthesis, such as isoniazid and ethionamide, have long been used as one of the most efficient drugs for the treatment of tuberculosis. However, the increasing cases of multidrug-resistant tuberculosis has urged the finding of new targets. In Mycobacterium, the acyl-CoA carboxylases (ACCase) provide the building blocks for both de novo fatty acid biosynthesis and further elongation to produce mycolic acids. Previous studies suggested that AccD6 is the carboxyltransferase component of the ACCase 6 enzyme complex implicated in the biosynthesis of malonyl-CoA. We have characterized a ligand, NCI-172033, previously identified as a weak inhibitor of another ACCase from M. tuberculosis. The compound competitively inhibited AccD6 and had a potent bactericidal activity against several pathogenic species of Mycobacterium. Inhibition of both fatty acid and mycolic acid biosynthesis at minimum inhibitory concentrations was also observed. These results help to define the biological roles of key ACCases in the biosynthesis of membrane and cell envelope fatty acids, and provide a new target, as well as a new lead, for the rational development of novel antimycobacterial drugs.