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Antimicrobial Agents and Chemotherapy, December 1998, p. 3097-3102, Vol. 42, No. 12
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.
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
*
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.
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