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

被引:217
作者
Wyllie, S
Cunningham, ML
Fairlamb, AH [1 ]
机构
[1] Univ Dundee, Sch Life Sci, Wellcome Trust Bioctr, Div Biol Chem & Mol Biol, Dundee DD1 5EH, Scotland
[2] Univ London London Sch Hyg & Trop Med, Dept Med Parasitol, London WC1E 7HT, England
基金
英国惠康基金;
关键词
D O I
10.1074/jbc.M405635200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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, 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.
引用
收藏
页码:39925 / 39932
页数:8
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