Drugs that Inhibit Mycolic Acid Biosynthesis in Mycobacterium tuberculosis - An Update

Basso, L. A.; Santos, D. S.
October 2005
Medicinal Chemistry Reviews - Online;Oct2005, Vol. 2 Issue 5, p393
Academic Journal
Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis, and infects approximately 32 % of the world's human population. It is estimated that 8.2 million new TB cases occurred worldwide in the year 2000, with approximately 1.8 million deaths in the same year, and more than 95 % of those were in developing countries. The interruption of centuries of decline in case rates of TB occurred, in most cases, in the late 1980s and involved the USA and some European countries due to increased poverty in urban settings and the immigration from TB high-burden countries. Thus, no sustainable control of TB epidemics can be reached in any country without properly addressing the global epidemic. The reemergence of TB as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, and the proliferation of multi-drug-resistant (MDR) strains have created much scientific interest in developing new antimycobacterial agents to both treat M. tuberculosis strains resistant to existing drugs, and shorten the duration of short-course treatment to improve patient compliance. Bacterial cell-wall biosynthesis is a proven target for new antibacterial drugs. Mycolic acids, which are key components of the mycobacterial cell wall, are a- alkyl, �-hydroxy fatty acids, with a species-dependent saturated "short" arm of 20-26 carbon atoms and a "long" meromycolic acid arm of 50-60 carbon atoms. The latter arm is functionalized at regular intervals by cyclopropyl, a-methyl ketone, or a-methyl methylethers groups, and, as shown more recently, by unsaturations. The mycolic acid biosynthetic pathway has been proposed to involve five distinct stages: (i) synthesis of C20 to C26 straightchain saturated fatty acids to provide the a-alkyl branch; (ii) synthesis of the meromycolic acid chain to provide the main carbon backbone, (iii) modification of this backbone to introduce other functional groups; (iv) the final Claisen-type condensation step followed by reduction; and (v) various mycolyltransferase processes to cellular lipids. The drugs shown to inhibit mycolic acid biosynthesis are isoniazid, ethionamide, isoxyl, thiolactomycin, and triclosan. Pyrazinamide was thought to inhibit fatty acid synthase type I, thereby reducing the synthesis of precursor of mycolic acids. However, current experimental evidence indicates that it has no defined target of action. The main focus of our contribution is on new data describing the mode of action of antitubercular drugs that inhibit mycolic acid biosynthesis, and description of inhibitors of fatty acid synthase type II enzymes as potential lead compounds that may allow the development of new antitubercular agents.


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