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Antimicrobial Agents and Chemotherapy, July 2001, p. 2064-2069, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2064-2069.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Antimonial-Mediated DNA Fragmentation in Leishmania infantum Amastigotes

Denis Sereno,1 Philippe Holzmuller,1 Isabelle Mangot,1 Gérard Cuny,3 Ali Ouaissi,2 and Jean-Loup Lemesre1,*

Laboratoire de Biologie Parasitaire,1 CJF-INSERM N°96/04,2 and Laboratoire de Parasitologie et Entomologie Moléculaire,3 Centre IRD (Institut de Recherche pour le Développement), 34032 Montpellier Cedex 1, France

Received 30 November 2000/Returned for modification 25 January 2001/Accepted 2 April 2001

The basic treatment of leishmaniasis consists in the administration of pentavalent antimonials. The mechanisms that contribute to pentavalent antimonial toxicity against the intracellular stage of the parasite (i.e., amastigote) are still unknown. In this study, the combined use of several techniques including DNA fragmentation assay and in situ and cytofluorometry terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling methods and YOPRO-1 staining allowed us to demonstrate that potassium antimonyl tartrate, an Sb(III)-containing drug, was able to induce cell death associated with DNA fragmentation in axenic amastigotes of Leishmania infantum at low concentrations (10 µg/ml). This observation was in close correlation with the toxicity of Sb(III) species against axenic amastigotes (50% inhibitory concentration of 4.75 µg/ml). Despite some similarities to apoptosis, nuclease activation was not a consequence of caspase-1, caspase-3, calpain, cysteine protease, or proteasome activation. Altogether, our results demonstrate that the antileishmanial toxicity of Sb(III) antimonials is associated with parasite oligonucleosomal DNA fragmentation, indicative of the occurrence of late events in the overall process of apoptosis. The elucidation of the biochemical pathways leading to cell death could allow the isolation of new therapeutic targets.

* Corresponding author. Mailing address: Laboratoire de Biologie Parasitaire, IRD, 911 Av. Agropolis, BP 5045, 34032 Montpellier Cedex 1, France. Phone: (33) 04 67 41 62 20. Fax: (33) 04 67 54 78 00. E-mail: Lemesre{at}mpl.ird.fr.

Antimicrobial Agents and Chemotherapy, July 2001, p. 2064-2069, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2064-2069.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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