title: Efficacy of second line drugs on antimonyl-resistant amastigotes of Leishmania infantum.
abstract: In a previous paper we have demonstrated that the induction, by direct drug pressure, of a resistance to Sb(III) antimony at physiological concentration in the amastigote stage of the parasite, led to a high cross-resistance to Sb(V) species in the form of Glucantime. In this paper, further chemoresistant clones were characterized. Axenic amastigotes of Leishmania infantum were adapted to survive in culture medium containing 4, 20, 30 and 120 microg/ml of potassium antimonyl tartrate Sb(II). These mutants were 12, 28, 35 and 44-fold more resistant to Sb(III) than the parental wild-type clone. They were able to resist at concentrations of Glucantime Sb(V) as high as 160 microg/ml when growing in THP-1 cells. We have investigated the efficacy of second line drugs in clinical use (pentamidine and amphotericin B) on the antimony-resistant mutants. Amphotericin B was toxic for both wild-type and chemoresistant mutants at concentrations ranging from 0.05 to 0.15 microM. Pentamidine which is extensively used when the first course of antimonial pentavalent compounds is unsuccessful, was more toxic for all the chemoresistant organisms than for the wild-type clone. In the same way, chemoresistant amastigotes growing within THP-1 cells were more susceptible to pentamidine than the wild-type clone. Our results showed that the resistance of the mutants was restricted to the antimony containing drugs and did not led to a cross-resistance against the other clinically relevant drugs. These results confirmed that these two drugs (pentamidine and amphotericin B) are good candidates to treat pentavalent antimonial unresponsiveness.
authors.affiliation: Laboratoire de Biologie Parasitaire, Institut de Recherche pour le Développement, Montpellier, France.
authors.forename: D
authors.initials: D
authors.lastname: Sereno
authors.forename: P
authors.initials: P
authors.lastname: Holzmuller
authors.forename: J L
authors.initials: JL
authors.lastname: Lemesre
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000966:Antimony Potassium Tartrate / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002460:Cell Line; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D018314:Leishmania infantum / Q000187:drug effects* / Q000235:genetics; D008536:Meglumine / Q000494:pharmacology*; D000077485:Meglumine Antimoniate; D009154:Mutation; D009942:Organometallic Compounds / Q000494:pharmacology*; D010419:Pentamidine / Q000494:pharmacology
chemical_list: D000981:Antiprotozoal Agents; D009942:Organometallic Compounds; D010419:Pentamidine; D008536:Meglumine; D000077485:Meglumine Antimoniate; D000666:Amphotericin B; D000966:Antimony Potassium Tartrate