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Antimicrobial Agents and Chemotherapy, November 2005, p. 4616-4621, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4616-4621.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Gene Expression Analysis of the Mechanism of Natural Sb(V) Resistance in Leishmania donovani Isolates from Nepal

Unit of Molecular Parasitology, Department of Parasitology, Prince Leopold Institute of Tropical Medicine, Antwerp B-2000,¹ Department of Biomedical Sciences, University of Antwerp, Antwerp B-2080, Belgium,² B. P. Koirala Institute of Health Sciences, Dharan, Nepal,³ Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E7HT, United Kingdom,⁴ Department of Community Medicine, Travel and Migration Medicine Unit, Hôpitaux Universitaires de Genève, Geneva, Switzerland⁵

Received 29 June 2005/ Returned for modification 27 July 2005/ Accepted 17 August 2005

Control of visceral leishmaniasis (VL) is being challenged by the emergence of natural resistance against the first line of treatment, pentavalent antimonials [Sb(V)]. An insight into the mechanism of natural Sb(V) resistance is required for the development of efficient strategies to monitor the emergence and spreading of Sb(V) resistance in countries where VL is endemic. In this work, we have focused on the mechanism of natural Sb(V) resistance emerging in Nepal, a site where anthroponotic VL is endemic. Based on the current knowledge of Sb(V) metabolism and of the in vitro trivalent antimonial [Sb(III)] models of resistance to Leishmania spp., we selected nine genes for a comparative transcriptomic study on natural Sb(V)-resistant and -sensitive Leishmania donovani isolates. Differential gene expression patterns were observed for the genes coding for 2-thiol biosynthetic enzymes, gamma-glutamylcysteine synthetase (GCS) and ornithine decarboxylase (ODC), and for the Sb(III) transport protein aquaglyceroporin 1 (AQP1). The results indicate that the mechanism for natural Sb(V) resistance partially differs from the mechanism reported for in vitro Sb(III) resistance. More specifically, we hypothesize that natural Sb(V) resistance results from (i) a changed thiol metabolism, possibly resulting in inhibition of Sb(V) activation in amastigotes, and (ii) decreased uptake of the active drug Sb(III) by amastigotes.

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