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Antimicrobial Agents and Chemotherapy, March 2008, p. 1080-1093, Vol. 52, No. 3
0066-4804/08/$08.00+0     doi:10.1128/AAC.01196-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Inhibition of ABC Transporters Abolishes Antimony Resistance in Leishmania Infection

Jayati Mookerjee Basu,^1,, Ananda Mookerjee,^2,, Rajdeep Banerjee,³ Manik Saha,⁴ Subhankar Singh,³ Ksudiram Naskar,¹ Gayetri Tripathy,¹ Prabhat K. Sinha,³ Krishna Pandey,³ Shyam Sundar,⁵ Sanjeev Bimal,³ Pradip K. Das,³ Soumitra K. Choudhuri,² and Syamal Roy^1*

Department of Immunology, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, WB, India,¹ Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata 700026, WB, India,² Rajendra Memorial Research Institute, Patna 800007, India,³ Geological Survey of India, Kolkata, India,⁴ Department of Medicine, Institute of Medical Sciences, Benaras Hindu University, Varanasi, India⁵

Received 11 September 2007/ Returned for modification 14 October 2007/ Accepted 16 November 2007

The emergence of antimony (Sb) resistance has jeopardized the treatment of visceral leishmaniasis in various countries. Previous studies have considered the part played by leishmanial parasites in antimony resistance, but the involvement of host factors in the clinical scenario remained to be investigated. Here we show that unlike infection with Sb-sensitive (Sb^s) Leishmania donovani, infection with Sb-resistant (Sb^r) L. donovani induces the upregulation of multidrug resistance-associated protein 1 (MRP1) and permeability glycoprotein (P-gp) in host cells, resulting in a nonaccumulation of intracellular Sb following treatment with sodium antimony gluconate (SAG) favoring parasite replication. The inhibition of MRP1 and P-gp with resistance-modifying agents such as lovastatin allows Sb accumulation and parasite killing within macrophages and offers protection in an animal model in which infection with Sb^r L. donovani is otherwise lethal. The occurrence of a similar scenario in clinical cases is supported by the findings that unlike monocytes from SAG-sensitive kala-azar (KA) patients, monocytes from SAG-unresponsive KA patients overexpress P-gp and MRP1 and fail to accumulate Sb following in vitro SAG treatment unless pretreated with inhibitors of ABC transporters. Thus, the expression status of MRP1 and P-gp in blood monocytes may be used as a diagnostic marker for Sb resistance and the treatment strategy can be designed accordingly. Our results also indicate that lovastatin, which can inhibit both P-gp and MRP1, might be beneficial for reverting Sb resistance in leishmaniasis as well as drug resistance in other clinical situations, including cancer.

Published ahead of print on 3 December 2007.

Present address: U563, INSERM, CHU Purpan, Toulouse, France.

These authors contributed equally.