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1. Pharmacological Modalities for the Treatment of Drug Resistant Tuberculosis: New Horizon

   • Rajakrishnan Vijayakrishnan, MD

   Saint Vincent Hospital, Worcester, Massachusetts

   TO THE EDITOR:

   I read with interest the article by Kliiman et al (1). The authors state that: “Any new drug developed to treat tuberculosis (which is rarely done) will rapidly become unusable because of developing resistance against it if public health does not ensure the drugs are correctly used. ....... the key issues are reducing relapses through proper detection and more successful treatment of new cases with adequate drug regimens and a patient-oriented approach to ensure adherence.” This statement holds true for conventional anti-tuberculous drugs which develop resistance after non -judicial use. We have conducted structure-based studies to design lead compounds which can be developed into drugs, to counter the resistance to Isoniazid (INH) – one of the key drugs in treatment of tuberculosis (2). The NADH–dependent Enoyl-ACP reductase (InhA), which is encoded by the Mycobacterium gene inhA, is a key enzyme in the biosynthesis of mycolic acids. It is now well established that InhA is the primary molecular target of Isoniazid (3).

   Isoniazid is a prodrug, which must first be activated by KatG, a catalase-peroxidase, to an acyl radical which covalently binds to the co- substrate for InhA, NADH (4). Resistance to INH is mediated mainly through mutations in the KatG gene (5). Therefore, direct inhibitors of InhA, which do not require activation, are suitable candidates for the development of new drugs against tuberculosis. Using a structure-based approach, we have identified a tripeptide inhibitor (100 times more potent than the existing inhibitors) which is a potential lead compound for the development of new anti-tuberculous drugs (2).

   The significance of such drug discovery lies in the fact that even when drug resistant M tuberculi, is identified it can be effectively treated by using these novel agents. There is a need for increased research at the molecular mechanisms of drug resistance in tuberculosis. Such novel drugs which can overcome drug resistance are a new horizon in the treatment of multi-drug resistant tuberculosis which still holds the largest morbidity and mortality caused by a single bacterial agent in the world.

   References

   1. Kliiman K, Altraja A. Predictors of extensively drug-resistant pulmonary tuberculosis. Ann Intern Med 2009;150(11):766-75.

   2. Subba Rao G, Vijayakrishnan R, Kumar M. Structure-based design of a novel class of potent inhibitors of InhA, the enoyl acyl carrier protein reductase from Mycobacterium tuberculosis: a computer modelling approach. Chem Biol Drug Des 2008;72(5):444-9.

   3. Banerjee A, Dubnau E, Quemard A et al. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 1994;263:227-30.

   4. Zhang Y, Heym B, Allen B, Young D, Cole S. The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 1992;358:591-3.

   5. Escalante P, Ramaswamy S, Sanabria H et al. Genotypic characterization of drug-resistant Mycobacterium tuberculosis isolates from Peru. Tuber Lung Dis 1998;79(2):111-8.

   Conflict of Interest:

   None declared

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   Published July 9, 2009