Identification of Saccharomyces cerevisiae genes conferring resistance to quinoline ring-containing antimalarial drugs.
To identify genes that can confer resistance to antimalarial drugs in yeast, we transformed the quinidine-sensitive strain CYX247-9A of Saccharomyces cerevisiae with a yeast genomic library and selected for transformants that grow in the presence of elevated levels of antimalarial drugs. Plasmids were rescued from such clones and were analyzed for the presence of individual open reading frames that can confer drug resistance. Using quinidine as the selective drug, we were able to identify three genes that can cause resistance to antimalarial drugs. Overexpression of the yeast genes CIN5 (a member of the family of bZIP transcription factors), STII (a Hsp90 cochaperone), and YOR273c (a member of the major facilitator superfamily of transmembrane transporters) conferred 3.9-, 7.0-, and 4.3-fold resistance to quinidine, respectively, over that of control yeast. Cross-resistance assays determined that STI1 also conferred resistance to mefloquine (3.4-fold), while CIN5 also conferred resistance to mefloquine (9.6-fold) and chloroquine (5.4-fold). Using mefloquine as the selective drug, we determined that overexpression of YBR233w, a member of the hnRNPK family of nuclear RNA binding proteins, conferred resistance to mefloquine (13.5-fold). Expression of the human hnRNPK homolog of YBR233w in S. cerevisiae also conferred mefloquine resistance, suggesting that homologs of the identified resistance genes may perform similar functions in species other than yeast. Our experiments have identified heretofore unknown pathways of resistance to quinoline ring-containing antimalarial drugs in S. cerevisiae.
Delling
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McGill Centre for the Study of Host Resistance, Department of Medicine, McGill University, Montréal General Hospital Research Institute, Québec, Canada.
Raymond
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Schurr
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D000595:Amino Acid Sequence; D000962:Antimalarials / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005800:Genes, Fungal / Q000235:genetics*; D015767:Mefloquine / Q000494:pharmacology; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D000962:Antimalarials; D015767:Mefloquine