ABSTRACT
One of the first approaches undertaken in the quest for antitubercular compounds was that of understanding the mechanism of action of old drugs and proposing chemical modifications or other strategies to improve their activity, generally lost to the mechanisms of resistance developed by Mycobacterium tuberculosis. A leading case was the work carried out on a set of compounds with proven activity on the essential pathway of the synthesis of mycolic acids. As a result, different solutions were presented, improving the activity of those inhibitors or producing novel compounds acting on the same molecular target(s), but avoiding the most common resistance strategies developed by the tubercle bacilli. This review focuses on the activity of those compounds, developed following the completion of the studies on several of the classic antitubercular drugs.
Subject(s)
Antitubercular Agents/chemical synthesis , Mycobacterium tuberculosis/drug effects , Mycolic Acids/antagonists & inhibitors , Antitubercular Agents/pharmacology , Drug Design , Drug Resistance, Multiple, Bacterial/drug effects , Ethionamide/analogs & derivatives , Ethionamide/chemical synthesis , Ethionamide/pharmacology , Humans , Isoniazid/analogs & derivatives , Isoniazid/chemical synthesis , Isoniazid/pharmacology , Mycobacterium tuberculosis/metabolism , Mycolic Acids/metabolism , Phenylthiourea/analogs & derivatives , Phenylthiourea/chemical synthesis , Phenylthiourea/pharmacology , Structure-Activity Relationship , Thioacetazone/analogs & derivatives , Thioacetazone/chemical synthesis , Thioacetazone/pharmacology , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/microbiologyABSTRACT
It has recently been shown that the anti-mycobacterial pro-drug thiacetazone (TAC) inhibits the conversion of double bonds of mycolic acid precursors into cyclopropyl rings in Mycobacterium bovis var BCG, M. marimum and M. chelonae by affecting the cyclopropyl mycolic acid synthases (CMASs) as judged by the build-up of unsaturated mycolate precursors. In our hands, TAC inhibits mycolic acid biosynthesis in Mycobacterium tuberculosis and M. kansasii with almost negligible accumulation of those precursors. Our observations that 'de novo' biosynthesis of all the mycolic acid families decreased upon TAC treatment prompted us to analyse the role of each one of the Type II Fatty Acid Synthase (FASII) enzymes. Overexpression of the hadABC operon, encoding the essential FASII dehydratase complex, but not of any of the remaining FASII genes acting on the elongation of fatty acyl chains leading to the synthesis of meromycolic acids, resulted in high level of resistance to TAC in M. tuberculosis. Spontaneous M. tuberculosis and M. kansasii TAC-resistant mutants isolated during this work revealed mutations in the hadABC genes strongly supporting our proposal that these enzymes are new players in the resistance to this anti-mycobacterial compound.