Gene expression profiling and molecular characterization of antimony resistance in Leishmania amazonensis

Drug resistance is a major problem in leishmaniasis chemotherapy. RNA expression profiling using DNA microarrays is a suitable approach to study simultaneous events leading to a drug-resistance phenotype. Genomic analysis has been performed primarily with Old World Leishmania species and here we inv...

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Bibliographic Details
Published in:PLoS neglected tropical diseases 2011-05, Vol.5 (5), p.e1167
Main Authors: do Monte-Neto, Rubens L, Coelho, Adriano C, Raymond, Frédéric, Légaré, Danielle, Corbeil, Jacques, Melo, Maria N, Frézard, Frédéric, Ouellette, Marc
Format: Article
Language:English
Subjects:
ABC transporters
Animals
Antimony
Antimony - toxicity
Antiprotozoal Agents - toxicity
Biology
Chemotherapy
Drug Resistance
Drug therapy
Experiments
Gene amplification
Gene expression
Gene Expression Profiling
Genetic aspects
Genomes
Health aspects
Humans
Leishmania mexicana - drug effects
Leishmania mexicana - genetics
Leishmaniasis
Medicine
Metabolic Networks and Pathways - genetics
Microarray Analysis
Parasites
Parasitic diseases
Polyamines
Tropical diseases
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Summary:Drug resistance is a major problem in leishmaniasis chemotherapy. RNA expression profiling using DNA microarrays is a suitable approach to study simultaneous events leading to a drug-resistance phenotype. Genomic analysis has been performed primarily with Old World Leishmania species and here we investigate molecular alterations in antimony resistance in the New World species L. amazonensis. We selected populations of L. amazonensis promastigotes for resistance to antimony by step-wise drug pressure. Gene expression of highly resistant mutants was studied using DNA microarrays. RNA expression profiling of antimony-resistant L. amazonensis revealed the overexpression of genes involved in drug resistance including the ABC transporter MRPA and several genes related to thiol metabolism. The MRPA overexpression was validated by quantitative real-time RT-PCR and further analysis revealed that this increased expression was correlated to gene amplification as part of extrachromosomal linear amplicons in some mutants and as part of supernumerary chromosomes in other mutants. The expression of several other genes encoding hypothetical proteins but also nucleobase and glucose transporter encoding genes were found to be modulated. Mechanisms classically found in Old World antimony resistant Leishmania were also highlighted in New World antimony-resistant L. amazonensis. These studies were useful to the identification of resistance molecular markers.
ISSN:1935-2735
1935-2727
1935-2735
DOI:10.1371/journal.pntd.0001167