A nucleoside transporter from Trypanosoma brucei involved in drug resistance.
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.
Swiss Tropical Institute, CH-4002 Basel, Switzerland. Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
P
P
Mäser
C
C
Sütterlin
A
A
Kralli
R
R
Kaminsky
D000241:Adenosine / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001152:Arsenicals / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D004351:Drug Resistance / Q000235:genetics; D017125:Genes, Protozoan; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D033703:Nucleoside Transport Proteins; D009705:Nucleosides / Q000378:metabolism; D011687:Purines / Q000378:metabolism / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013379:Substrate Specificity; D014344:Trypanocidal Agents / Q000378:metabolism / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology
D001152:Arsenicals; D002352:Carrier Proteins; D008565:Membrane Proteins; D033703:Nucleoside Transport Proteins; D009705:Nucleosides; D011687:Purines; D014344:Trypanocidal Agents; C044719:melarsen oxide; D000241:Adenosine