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Am. J. Trop. Med. Hyg., 76(4), 2007, pp. 681-688
Copyright © 2007 by The American Society of Tropical Medicine and Hygiene

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CHARACTERIZATION OF NATURAL ANTIMONY RESISTANCE IN LEISHMANIA DONOVANI ISOLATES

MUKUL K. MITTAL, SMITA RAI, ASHUTOSH, RAVINDER, SUMAN GUPTA, SHYAM SUNDAR, AND NEENA GOYAL*
Division of Biochemistry and Division of Parasitology, Central Drug Research Institute, Lucknow, India; Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

Clinical resistance to pentavalent antimonial compounds has long been recognized as a major problem in the treatment of visceral leishmaniasis in India. However, mechanisms of natural resistance are unclear. In this study, we observed that Leishmania donovani clinical isolates not responsive to sodium stibogluconate showed resistance to antimony treatment in both in vitro and in vivo laboratory conditions. The resistant isolates have increased levels of intracellular thiols. This increase in thiol levels was not mediated by the amplification of {gamma}-glutamylcysteine synthetase, but was accompanied by amplification of trypanothione reductase and an intracellular ATP-binding cassette transporter gene MRPA. The resistance of parasites to antimony could be reversed by the glutathione biosynthesis-specific inhibitor, buthionine sulfoximine, which resulted in increased drug susceptibility. These results suggest the possible role of thiols and MRPA in antimony resistance in field isolates.

Received September 12, 2006. Accepted for publication November 22, 2006.

Acknowledgments: We thank Dr. M. Ouellette for providing the MRPA and {gamma}-GCS1 probe and A. Kauser for computational help.

Financial support: This work was supported by the Department of Biotechnology (grant no. BT/PR2792/Med/14/383/2001), India. Mukul K. Mittal and Ashutosh Ravinder were supported by the Council of Scientific and Industrial Research, India, and Smita Rai was supported by the Department of Biotechnology, India. The American Society of Tropical Medicine and Hygiene (ASTMH) assisted with publication expenses.

* Address correspondence to Neena Goyal, Division of Biochemistry, Central Drug Research Institute, Lucknow 226001, India. E-mail: neenacdri{at}yahoo.com

Authors’ addresses: Mukul K. Mittal, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN 37232-7560. Smita Rai, Ashutosh, Ravinder, and Neena Goyal, Division of Biochemistry, Central Drug Research Institute, Lucknow 226001, India, Telephone: 91-522-2625932, Fax: 91-522-262-3938 and 91-522-262-3405, E-mail: neenacdri{at}yahoo.com. Suman Gupta, Division of Parasitology, Central Drug Research Institute, Lucknow 226001, India. Shyam Sundar, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.




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