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

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2005 Oct 28

PMID 16251303

Citations 62

Authors

Saskia Decuypere

Suman Rijal

Vanessa Yardley

Simonne De Doncker

Thierry Laurent

Basudha Khanal

Francois Chappuis

Jean-Claude Dujardin

Affiliations

Soon will be listed here.

Abstract

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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