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

Abstract

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 α-alkyl, β-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, α-methyl ketone, or α-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 α-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.

Shikimate Kinase: A Potential Target for Development of Novel Antitubercular Agents

“…A key driver of the increase is the synergy with the HIV epidemic, which is having a devastating impact on some parts of the world mostly in the African Region, where 31% of new TB cases were attributable to HIV co-infection [50]. Another problem is the proliferation of multi-drug resistant (MDR) strains, defined as resistants to at least isoniazid and rifampicin, which are the most effective first-line drugs [53]. According to the 2004 Global TB Control Report of the World Health Organization, there are 300,000 new cases per year of MDR-TB worldwide, and 79 % of MDR-TB cases are now "super strains", resistant to at least three of the four main drugs used to treat TB [52].…”

“…No new classes of drugs for TB have been developed in the past 30 years, reflecting the inherent difficulties in discovery and clinical testing of new agents and the lack of pharmaceutical industry in investing money and manpower for research in the area [55]. Hence, there is an urgent need to developing faster acting and effective new antitubercular agents, preferably belonging to new structural classes, to better combat TB, including MDR-TB, to shorten the duration of current treatment to improve patient compliance, and to provide effective treatment of latent tuberculosis infection [53].…”

Crystallographic studies on the binding of isonicotinyl-NAD adduct to wild-type and isoniazid resistant 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis

“…The mechanism of action of isoniazid is complex, as mutations in at least five different genes (katG, inhA, ahpC, kasA, and ndh) have been found to correlate with isoniazid resistance (Schroeder et al, 2002;Blanchard, 1996;Glickman and Jacobs, 2001;Basso and Santos, 2005;Oliveira et al, 2007). Consistent with InhA as the primary target of INH mode of action, INHresistant clinical isolates of M. tuberculosis harboring inhA-structural gene missense mutations, but lacking mutations in the inhA promoter region, katG gene and oxyRahpC region, were shown to have higher dissociation constant (K d ) values for NADH than INH-sensitive WT InhA, whereas there were only modest differences in the steady-state parameters (Blanchard, 1996).…”

Functional Characterization by Genetic Complementation of aroB -Encoded Dehydroquinate Synthase from Mycobacterium tuberculosis H37Rv and Its Heterologous Expression and Purification

“…The World Health Organization has estimated that 9 million people are infected per year, leading to 2 million deaths, mainly in sub-Saharan Africa and Asia (39). The discovery of the antibacterial and antituberculosis properties of streptomycin, isoniazid, and pyrazinamide led to effective chemotherapy that decreased the TB mortality rate worldwide (1). The later introduction of ethionamide, rifampin, ethambutol, and ciprofloxacin to the arsenal for TB treatment seemed to provide an adequate number of effective antimicrobial agents.…”