Current status and approaches to tuberculosis drug development

Tuberculosis (TB), which kills more people than any other infectious disease, was declared a global emergency by the World Health Organization in 1993. The emergence of new Mycobacterium tuberculosis strains that are resistant to some or all current antitubercular drugs seriously hampers the control of the disease. Up to 50 million people may be infected with drug-resistant TB, with resistance being caused by inconsistent or partial treatment when patients do not comply with long-term chemotherapy. Resistance is often a corollary to HIV infection. Besides being more fatal, drug-resistant TB is more difficult and more expensive to treat. in addition to this human cost, TB also represents a significant economic burden for developing countries. Therefore, new approaches to the treatment of TB are needed. During the last few years, important efforts have been made in order to elucidate the molecular mechanism of action of antitubercular drugs and understand the genetic basis of acquired drug resistance in M. tuberculosis. The identification of novel targets requires the characterisation of biochemical pathways specific to mycobacteria. Many unique metabolic processes occur during the biosynthesis of cell wall components, including arabinogalactan and mycolic acids. In this review, the mode of action of first- and second-line agents, as well as the potentiality of some promising drugs that are still at an early stage of development will be described. Finally, some of the attractive targets offered by the mycobacterial cell wall for the rational design of new antitubercular drugs for a future and more effective control of the disease will be examined.