JAC Advance Access published online on January 9, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl494
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Role of ABC transporter MRPA, 
-glutamylcysteine synthetase and ornithine decarboxylase in natural antimony-resistant isolates of Leishmania donovani
1 School of Life Sciences, Jawaharlal Nehru University, New Delhi – 110 067, India 2 Centre de Recherche en Infectologie du Centre De Recherche du CHUL and Department of Microbiologie, Faculté de Médecine, Université Laval, Québec, Canada 3 Department of Pharmacology, Institute of Postgraduate Medical Education & Research, 244B Acharya JC Bose Road, Kolkata – 700 02, India
Received 23 August 2006; returned 27 October 2006; revised 6 November 2006; accepted 12 November 2006
* Corresponding author. Tel: +91-11-26106630; Fax: +91-11-26165886; E-mail: madhubala{at}mail.jnu.ac.in
OBJECTIVES: The resistance of clinical isolates of Leishmania donovani to sodium antimony gluconate (SAG), the mainstay of treatment in Indian visceral leishmaniasis, has become a critical issue in India. The present work investigates the mechanism of resistance to SAG in parasites isolated from patients who are unresponsive to SAG.
METHODS AND RESULTS: Susceptibility to SAG as determined in vitro with intracellular amastigotes correlated well with the clinical response. The ABC transporter gene MRPA was amplified in resistant field isolates as part of an extrachromosomal circle. Co-amplification of the pterin reductase gene (PTR1) and MRPA suggests amplification of the H locus in SAG-resistant isolates. Amplification of MRPA was correlated to increased RNA as determined by real-time PCR. MRPA is an ABC-thiol transporter, and cysteine and glutathione were increased in the resistant isolates. Ornithine decarboxylase (a rate limiting enzyme in polyamine biosynthesis), and 
-glutamylcysteine synthetase (a rate limiting enzyme in glutathione biosynthesis), the two building blocks of the main cellular thiol trypanothione, were overexpressed in some of the resistant isolates.
CONCLUSIONS: A variety of resistance mechanisms to SAG, most of them consistent with a model based on the study of resistance in vitro, were present in clinical isolates from the same geographical region.
Key Words: drug resistance , sodium antimony gluconate , Leishmania donovani
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