Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani.
Despite extensive use of antimonial compounds in the treatment of leishmaniasis, their mode of action remains uncertain. Here we show that trivalent antimony (Sb(III)) interferes with trypanothione metabolism in drug-sensitive Leishmania parasites by two inherently distinct mechanisms. First, Sb(III) decreases thiol buffering capacity by inducing rapid efflux of intracellular trypanothione and glutathione in approximately equimolar amounts. Second, Sb(III) inhibits trypanothione reductase in intact cells resulting in accumulation of the disulfide forms of trypanothione and glutathione. These two mechanisms combine to profoundly compromise the thiol redox potential in both amastigote and promastigote stages of the life cycle. Furthermore, we demonstrate that sodium stibogluconate, a pentavalent antimonial used clinically for the treatment for leishmaniasis, induces similar effects on thiol redox metabolism in axenically cultured amastigotes. These observations suggest ways in which current antimony therapies could be improved, overcoming the growing problem of antimony resistance.
Wyllie
Susan
S
Division of Biological Chemistry and Molecular Biology, Wellcome Trust Biocentre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
Cunningham
Mark L
ML
Fairlamb
Alan H
AH
D000818:Animals; D000965:Antimony / Q000494:pharmacology; D000967:Antimony Sodium Gluconate / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D006224:Cricetinae; D004220:Disulfides / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D007896:Leishmaniasis / Q000188:drug therapy*; D008647:Mesocricetus; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D000981:Antiprotozoal Agents; D004220:Disulfides; D013438:Sulfhydryl Compounds; D000965:Antimony; D000967:Antimony Sodium Gluconate