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Antimicrobial Agents and Chemotherapy, May 1998, p. 1034-1041, Vol. 42, No. 5
McGill Centre for the Study of Host
Resistance,
Received 7 January 1998/Returned for modification 29 January
1998/Accepted 12 February 1998
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), STI1 (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.
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Identification of Saccharomyces
cerevisiae Genes Conferring Resistance to Quinoline
Ring-Containing Antimalarial Drugs
*
Corresponding author. Mailing address: McGill Centre
for the Study of Host Resistance, Montreal General Hospital Research Institute, 1650 Cedar Ave., Montreal, Quebec H3G 1A4, Canada. Phone:
(514) 937-6011, ext. 4513. Fax: (514) 933-7146. E-mail: erwin{at}igloo.epi.mcgill.ca.
Antimicrobial Agents and Chemotherapy, May 1998, p. 1034-1041, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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