Abstract
Drug resistance of pathogens is an increasing problem whose underlying mechanisms are not fully understood. Cellular uptake of the major drugs against Trypanosoma brucei spp., the causative agents of sleeping sickness, is thought to occur through an unusual, so far unidentified adenosine transporter. Saccharomyces cerevisiae was used in a functional screen to clone a gene (TbAT1) from Trypanosoma brucei brucei that encodes a nucleoside transporter. When expressed in yeast, TbAT1 enabled adenosine uptake and conferred susceptibility to melaminophenyl arsenicals. Drug-resistant trypanosomes harbor a defective TbAT1 variant. The molecular identification of the entry route of trypanocides opens the way to approaches for diagnosis and treatment of drug-resistant sleeping sickness.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine / metabolism*
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Amino Acid Sequence
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Animals
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Arsenicals / metabolism
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Arsenicals / pharmacology
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Biological Transport
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Carrier Proteins / chemistry
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cloning, Molecular
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Drug Resistance / genetics
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Genes, Protozoan
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Membrane Proteins / chemistry
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Molecular Sequence Data
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Mutation
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Nucleoside Transport Proteins
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Nucleosides / metabolism
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Purines / metabolism
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Purines / pharmacology
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Saccharomyces cerevisiae / genetics
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Substrate Specificity
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Trypanocidal Agents / metabolism
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Trypanocidal Agents / pharmacology*
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Trypanosoma brucei brucei / drug effects*
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Trypanosoma brucei brucei / genetics
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Trypanosoma brucei brucei / metabolism*
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Trypanosomiasis, African / drug therapy
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Trypanosomiasis, African / parasitology
Substances
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Arsenicals
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Carrier Proteins
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Membrane Proteins
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Nucleoside Transport Proteins
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Nucleosides
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Purines
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Trypanocidal Agents
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melarsen oxide
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Adenosine
Associated data
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GENBANK/AF152369
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GENBANK/AF152370