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Role of Aquaglyceroporin (AQP1) Gene and Drug Uptake in Antimony-resistant Clinical Isolates of Leishmania donovani

Antimonial-containing drugs are the first line of treatment against Leishmaniasis. Resistance to antimonials in Leishmania is proposed to be due to reduced uptake of trivalent antimony (SbIII) through the aquaglyceroporin (AQP1). We investigated the uptake of SbIII and involvement of aquaglyceroporin in developing antimony resistance phenotype in Leishmania donovani clinical isolates. SbIII accumulation, copy number of AQP1 gene, and transcript levels were compared in antimony-sensitive versus -resistant isolates. Antimony-resistant field isolates showed reduced uptake of SbIII. The copy number of AQP1 gene showed higher copy number in the antimony-resistant isolates when compared with the sensitive isolates and did not correlate to the reduced uptake of SbIII. Downregulation of AQP1 RNA levels was not consistently found in the antimony-resistant isolates. Our studies indicate that while downregulation of AQP1 may be one of the mechanisms of antimony resistance, it is however not an invariable feature.

Received June 18, 2007. Accepted for publication February 15, 2008.

Acknowledgments: The work carried out in this paper was supported by a grant from the Council of Scientific and Industrial Research, Government of India, New Delhi, India to Rentala Madhubala. Mahendra Maharjan is supported by Tribhuvan University, Nepal. A Senior Research Fellowship from the Council of Scientific and Industrial Research, India supported SS. Mitali Chatterjee is grateful to S. Duttagupta and S. Roy, Indian Institute of Chemical Biology, Kolkata as also N. Singh, Central Drug Research Institute, Lucknow, India for kindly providing these strains. ICP-MS was done by ARBRO Analytical Division, New Delhi, India. The authors thank Marc Ouellette, Canada, for his valuable suggestions. The authors thank Mike Barrett, University of Glasgow, for his helpful suggestions.

Financial support: The work carried out in this paper was supported by a grant from the Council of Scientific and Industrial Research, Government of India, New Delhi, India to Rentala Madhubala.

^* Address correspondence to Rentala Madhubala, School of Life Sciences, Jawaharlal Nehru University, New Delhi – 110067 India. E-mail: madhubala{at}mail.jnu.ac.in

Authors’ addresses: Mahendra Maharjan, Sushma Singh, and Rentala Madhubala, School of Life Sciences, Jawaharlal Nehru University, New Delhi-110067, India, Tel: +91-11-26106630, Fax: 91-11-26106630, E-mails: mahendra_maharjan{at}yahoo.ca, sushmasingh76{at}yahoo.com, and madhubala{at}mail.jnu.ac.in. Mitali Chatterjee, Department of Pharmacology, Institute of Postgraduate Medical Education and Research, 244B Acharya JC Bose Road, Kolkata-700 02, India, Tel: +0-88-983-003-1523, E-mail: mitali4135{at}dataone.in,