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      Trypanothione overproduction and resistance to antimonials and arsenicals in Leishmania.

      Proceedings of the National Academy of Sciences of the United States of America
      Animals, Antimony Sodium Gluconate, toxicity, Antiprotozoal Agents, Arsenic Poisoning, Chromatography, High Pressure Liquid, Cysteine, metabolism, Drug Resistance, genetics, Glutathione, analogs & derivatives, biosynthesis, Leishmania, drug effects, Models, Biological, Mutation, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Spermidine

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          Abstract

          Leishmania resistant to arsenicals and antimonials extrude arsenite. Previous results of arsenite uptake into plasma membrane-enriched vesicles suggested that the transported species is a thiol adduct of arsenite. In this paper, we demonstrate that promastigotes of arsenite-resistant Leishmania tarentolae have increased levels of intracellular thiols. High-pressure liquid chromatography of the total thiols showed that a single peak of material was elevated almost 40-fold. The major species in this peak was identified by matrix-assisted laser desorption/ionization mass spectrometry as N1,N8-bis-(glutathionyl)spermidine (trypanothione). The trypanothione adduct of arsenite was effectively transported by the As-thiol pump. No difference in pump activity was observed in wild type and mutants. A model for drug resistance is proposed in which Sb(V)/As(V)-containing compounds, including the antileishmanial drug Pentostam, are reduced intracellularly to Sb(III)/As(III), conjugated to trypanothione, and extruded by the As-thiol pump. The rate-limiting step in resistance is proposed to be formation of the metalloid-thiol pump substrates, so that increased synthesis of trypanothione produces resistance. Increased synthesis of the substrate rather than an increase in the number of pump molecules is a novel mechanism for drug resistance.

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