©2007 Copyright Landes Bioscience. Not for Distribution. CHAPTER *Corresponding Author: Hemanta K. Majumder—Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, 4 Raja S.C Mullick Road, Kolkata-700032, India. Email: hkmajumder@iicb.res.in Drug Targets in Kinetoplastid Parasites , edited by Hemanta K. Majumder. ©2007 Landes Bioscience. DNA Topoisomerases of Leishmania : The Potential Targets for Anti-Leishmanial Therapy Benu Brata Das, Agneyo Ganguly and Hemanta K. Majumder* Summary P rotozoan parasites of the genus Leishmania cause severe diseases that threaten human beings, both for the high mortality rates involved and the economic loss resulting from morbidity, primarily in the tropical and subtropical areas. This ancient eukaryote shows variable genetic diversity in their life cycle, wherein DNA topoisomerases play a key role in cellular processes affecting the topology and organization of intracellular DNA. Kinetoplastid topoisomerases offer most attractive targets for their structural diversity from other eukaryotic counterpart and their indispensable function in cell biology. Therefore, understanding the bi- ology of kinetoplastid topoisomerases and the components and steps involved in this intricate process provide opportunities for target based drug designing against protozoan parasitic diseases. Introduction Leishmaniasis is a disease complex caused by 17 different species of protozoan parasites belonging to the genus Leishmania. The parasites are transmitted between mammalian hosts by phlebotomine sandflies. There are an estimated 12 million humans infected, with an incidence of 0.5 million cases of the visceral form of the disease and 1.5 to 2.0 million cases of the cutaneous form of the disease. Leishmaniasis has a worldwide distribution with important foci of infection in Central and South America, Southern Europe, North and East Africa, the Middle East, and the Indian subcontinent. Currently the main foci of visceral leishmaniasis (VL) are in Sudan and India and those of cutaneous leishmaniasis (CL) are in Afghanistan, Syria, and Brazil. In addition to the two major clinical forms of the disease, VL and CL, there are other cutaneous manifestations, including mucocutaneous leishmaniasis (MCL), diffuse cutaneous leishmaniasis (DCL), recidivans leishmaniasis (LR), and post-kala-azar dermal leishmaniasis (PKDL) that are often linked to host immune status. The number of cases of leishmaniasis is probably under estimated as leishmaniasis is a reportable disease in only 40 of the 88 countries where it is known to be present. 1 Although the global burden of leishmaniasis has remained stable for several years, the patterns of the disease change continiously. With increasing num- bers of human immunodeficiency virus (HIV) coinfections, human migration, and resettle- ment, there is a possibility of resurgence of the disease. 1 Improved approaches to diagnosis, vaccine development, vector and reservoir control and new drugs for treatment are still required. To make the situation even worse, some parasite strains have also developed resistance against the classical antimonial drugs, like sodium stibogluconate and megalumine antimonite. The second line of drugs, amphotericin B and pentamidines, although used clinically are very toxic.