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Antimicrobial Agents and Chemotherapy, December 1998, p. 3097-3102, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Axenically Grown Amastigotes of Leishmania infantum Used as an In Vitro Model To Investigate the Pentavalent Antimony Mode of Action

D. Sereno,1 M. Cavaleyra,1 K. Zemzoumi,2 S. Maquaire,1 A. Ouaissi,2 and J. L. Lemesre1,*

Laboratoire de Biologie Parasitaire1 and CJF-INSERM No. 96/04,2 Centre ORSTOM, 34 032 Montpellier Cedex 1, France

Received 9 April 1998/Returned for modification 18 May 1998/Accepted 28 September 1998

The mechanism(s) of activity of pentavalent antimony [Sb(V)] is poorly understood. In a recent study, we have shown that potassium antimonyl tartrate, a trivalent antimonial [Sb(III)], was substantially more potent than Sb(V) against both promastigotes and axenically grown amastigotes of three Leishmania species, supporting the idea of an in vivo metabolic conversion of Sb(V) into Sb(III). We report that amastigotes of Leishmania infantum cultured under axenic conditions were poorly susceptible to meglumine [Glucantime; an Sb(V)], unlike those growing inside THP-1 cells (50% inhibitory concentrations [IC50s], about 1.8 mg/ml and 22 µg/ml, respectively). In order to define more precisely the mode of action of Sb(V) agents in vivo, we first induced in vitro Sb(III) resistance by direct drug pressure on axenically grown amastigotes of L. infantum. Then we determined the susceptibilities of both extracellular and intracellular chemoresistant amastigotes to the Sb(V)-containing drugs meglumine and sodium stibogluconate plus m-chlorocresol (Pentostam). The chemoresistant amastigotes LdiR2, LdiR10, and LdiR20 were 14, 26, and 32 times more resistant to Sb(III), respectively, than the wild-type one (LdiWT). In accordance with the hypothesis described above, we found that intracellular chemoresistant amastigotes were resistant to meglumine [Sb(V)] in proportion to the initial level of Sb(III)-induced resistance. By contrast, Sb(III)-resistant cells were very susceptible to sodium stibogluconate. This lack of cross-resistance is probably due to the presence in this reagent of m-chlorocresol, which we found to be more toxic than Sb(III) to L. infantum amastigotes (IC50s, of 0.54 and 1.32 µg/ml, respectively). Collectively, these results were consistent with the hypothesis of an intramacrophagic metabolic conversion of Sb(V) into trivalent compounds, which in turn became readily toxic to the Leishmania amastigote stage.

* Corresponding author. Mailing address: Laboratoire de Biologie Parasitaire, ORSTOM, 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}melusine.mpl.orstom.fr.

Antimicrobial Agents and Chemotherapy, December 1998, p. 3097-3102, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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