Recent Advances in Antituberculous Drug Development and Novel Drug Targets

Haruaki Tomioka, PhD; Yutaka Tatano, PhD; Ko Yasumoto, PhD; Toshiaki Shimizu, PhD

Disclosures

Expert Rev Resp Med. 2008;2(4):455-471. 

In This Article

Expert Commentary

In order to combat intractable TB, especially MDR- and XDR-TB, the development of new classes of drugs exhibiting potent anti-MTB activity without crossresistance to the existing anti-tuberculous drugs is urgently required. For this purpose, it is necessary to accelerate investigations to identify new types of anti-TB drugs acting on novel drug targets. In particular, it is essential to develop active agents that are potently bactericidal against persistent and dormant organisms of MTB, in order to shorten the duration of directly observed treatment, short-course of TB patients and to eliminate the reservoir of MTB, especially in developing countries. The entire genome of MTB has been elucidated and, moreover, a number of mycobacterial virulence genes have been cloned and examined regarding their roles in the manifestation of mycobacterial pathogenicity in hosts. For instance, enzymes (e.g., PcaA, MmaA4, Msh, Fad, Pim, PapA5 and MmpL7 proteins) participating in the biosynthesis of cell wall components with extremely tight and rigid structures are promising targets for new drugs against MTB, which can survive and grow in host macrophages via the aid of its strong cell wall. In addition, enzymes in the glyoxylate shunt pathway (e.g., Icl, AceA and GlcB proteins) are useful targets for the structural design of agents active against both persistent and dormant types of MTB. At present, as new drug targets for anti-TB agents, the high-resolution structures of gene products encoded by virulence genes are now available, and structure-based inhibitor design is now underway, with the prospect of generating new classes of drugs that are potently active against MTB. Such structural bioinformatics-based approaches are very promising as a strategy to identify new classes of anti-tuberculous drugs.

There are a number of constraints that have deterred companies from making efforts to develop new anti-TB drugs. The time needed to develop any new anti-TB drug is long and involves huge expense, and there is a perceived lack of commercial return, because more than 95% of TB cases worldwide are in developing countries. However, we must remember the important fact that TB remains the most frequent and important infectious disease regarding morbidity and mortality in the world. Indeed, a third of the world's population is infected with MTB, and the prevalence is much higher in developing countries than in advanced nations. Thus, the most urgent goal of chemotherapy for TB, especially TB associated with HIV infection, is to develop highly active but low-cost drugs that can be used not only in industrialized but also developing countries, where the incidence of AIDS-associated, intractable TB is now rapidly increasing. It should be noted that over 95% of TB cases worldwide occur in developing nations, and that some of these countries suffer from an extremely high prevalence of HIV infection. This problem should be tackled via the development of such new anti-TB drugs with the global cooperation of medical researchers, pharmaceutical companies and public agencies.

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