antimony-potassium-tartrate and Leishmaniasis

In the present study, we selected in vitro populations of Leishmania Viannia guyanensis, L.V. braziliensis, L. Leishmania amazonensis and L.L. infantum chagasi that were resistant to potassium antimony tartrate (SbIII). The resistance index of these populations varied from 4- to 20-fold higher than that of their wild-type counterparts. To evaluate the stability of the resistance phenotype, these four resistant populations were passaged 37 to 47 times in a culture medium without SbIII. No change was observed in the resistance indexes of L.V. guyanensis (19-fold) and L.L. infantum chagasi (4-fold). In contrast, a decrease in the resistance index was observed for L.V. braziliensis (from 20- to 10-fold) and L.L. amazonensis (from 6- to 3-fold). None of the antimony-resistant populations exhibited cross-resistance to amphotericin B and miltefosine. However, the resistant populations of L.V. braziliensis, L.L. amazonensis and L.L. infantum chagasi were also resistant to paromomycin. A drastic reduction was observed in the infectivity in mice for the resistant L.V. guyanensis, L.L. amazonensis and L.V. braziliensis populations. The SbIII-resistant phenotype of L.V. braziliensis was stable after one passage in mice. Although the protocol of induction was the same, the SbIII-resistant populations showed different degrees of tolerance, stability, infectivity in mice and cross-resistance to antileishmanial drugs, depending on the Leishmania species.

Topics: Amphotericin B; Animals; Antimony Potassium Tartrate; Antiprotozoal Agents; Culture Media; Drug Resistance; Inhibitory Concentration 50; Leishmania; Leishmaniasis; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Paromomycin; Phenotype; Phosphorylcholine; Selection, Genetic; Serial Passage; Spleen; Virulence

Antimony-containing drugs are still the drugs of choice in the treatment of infections caused by the parasite Leishmania. Resistance to antimony is now common in some parts of the world, and several mechanisms of resistance have been described. By transfecting cosmid banks and selecting with potassium antimonyl tartrate (SbIII), we have isolated a cosmid associated with resistance. This cosmid contains 2 copies of the heat shock protein 70 (HSP70) and 1 copy of the heat shock cognate protein 70 (HSC70). Several data linked HSP70 to antimony response and resistance. First, several Leishmania species, both as promastigotes and amastigotes, increased the expression of their HSP70 proteins when grown in the presence of 1 or 2 times the Effect Concentration 50% of SbIII. In several mutants selected for resistance to either SbIII or to the related metal arsenite, the HSP70 proteins were found to be overexpressed. This increase was also observed in revertant cells grown for several passages in the absence of SbIII, suggesting that this increased production of HSP70 is stable. Transfection of HSP70 or HSC70 in Leishmania cells does not confer resistance directly, though these transfectants were better able to tolerate a shock with SbIII. Our results are consistent with HSP70 and HSC70 being a first line of defense against SbIII until more specific and efficient resistance mechanisms take over.

Topics: Animals; Antimony; Antimony Potassium Tartrate; Cosmids; Dose-Response Relationship, Drug; Drug Resistance; Gene Expression; HSC70 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Leishmania; Leishmaniasis; Stress, Physiological; Transfection

Topics: Administration, Topical; Antimony; Antimony Potassium Tartrate; Drug Therapy, Combination; Ketoconazole; Leishmaniasis; Male; Military Personnel; Panama Canal Zone

Topics: Antimony; Antimony Potassium Tartrate; Humans; Leishmaniasis; Leishmaniasis, Cutaneous; Leishmaniasis, Mucocutaneous; Succinates; United States