Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani

Susan Wyllie, Mark L. Cunningham, Alan H. Fairlamb

    Research output: Contribution to journalArticle

    194 Citations (Scopus)

    Abstract

    NOTE: THE CHARACTERS (SbIII) IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE ABSTRACT ON THE PUBLISHER’S WEBSITE FOR AN ACCURATE DISPLAY. Despite extensive use of antimonial compounds in the treatment of leishmaniasis, their mode of action remains uncertain. Here we show that trivalent antimony (SbIII) interferes with trypanothione metabolism in drug-sensitive Leishmania parasites by two inherently distinct mechanisms. First, SbIII decreases thiol buffering capacity by inducing rapid efflux of intracellular trypanothione and glutathione in approximately equimolar amounts. Second, SbIII 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.
    Original languageEnglish
    Pages (from-to)39925-39932
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume279
    Issue number38
    DOIs
    Publication statusPublished - 2004

    Fingerprint

    Leishmania donovani
    Antimony
    Pathogens
    Sulfhydryl Compounds
    Metabolism
    Oxidation-Reduction
    Leishmaniasis
    Glutathione
    Antimony Sodium Gluconate
    Pharmaceutical Preparations
    Leishmania
    Life Cycle Stages
    Disulfides
    Websites
    Life cycle
    Parasites
    Display devices
    trypanothione
    Therapeutics

    Cite this

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    title = "Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani",
    abstract = "NOTE: THE CHARACTERS (SbIII) IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE ABSTRACT ON THE PUBLISHER’S WEBSITE FOR AN ACCURATE DISPLAY. Despite extensive use of antimonial compounds in the treatment of leishmaniasis, their mode of action remains uncertain. Here we show that trivalent antimony (SbIII) interferes with trypanothione metabolism in drug-sensitive Leishmania parasites by two inherently distinct mechanisms. First, SbIII decreases thiol buffering capacity by inducing rapid efflux of intracellular trypanothione and glutathione in approximately equimolar amounts. Second, SbIII 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.",
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    Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani. / Wyllie, Susan; Cunningham, Mark L.; Fairlamb, Alan H.

    In: Journal of Biological Chemistry, Vol. 279, No. 38, 2004, p. 39925-39932.

    Research output: Contribution to journalArticle

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    AU - Wyllie, Susan

    AU - Cunningham, Mark L.

    AU - Fairlamb, Alan H.

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