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Antimicrobial Agents and Chemotherapy, July 2005, p. 2701-2709, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2701-2709.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Differential Gene Expression in Benznidazole-Resistant Trypanosoma cruzi Parasites

Diana Villarreal,¹ Philippe Nirdé,^2, Mallorie Hide,^1, Christian Barnabé,¹ and Michel Tibayrenc^1*

Génétique et Evolution des Maladies Infectieuses G.E.M.I., UMR 2724 CNRS/IRD, UR 165 IRD, Centre de Recherche IRD Montpellier, 911 Av. Agropolis BP 64501, 34394 Montpellier Cedex 5, France,¹ INSERM U540. 60, rue de Navacelles, 34090 Montpellier Cedex 5, France²

Received 15 December 2004/ Returned for modification 16 January 2005/ Accepted 21 February 2005

We analyzed the differential gene expression among representative Trypanosoma cruzi stocks in relation to benznidazole exposures using a random differentially expressed sequences (RADES) technique. Studies were carried out with drug pressure both at the natural susceptibility level of the wild-type parasite (50% inhibitory concentration for the wild type) and at different resistance levels. The pattern of differential gene expression performed with resistant stocks was compared to the population structure of this parasite, established by random amplified polymorphic DNA analysis and multilocus enzyme electrophoresis. A RADES band polymorphism was observed, and over- or underexpression was linked to the resistance level of the stock. The analysis of RADES bands suggested that different products may be involved in benznidazole resistance mechanisms. No significant association was found between phylogenetic clustering and benznidazole susceptibility. Benznidazole resistance may involve several mechanisms, depending on the level of drug exposure.

P. Nirdé and M. Hide contributed equally to this work.