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Eukaryotic Cell, August 2006, p. 1243-1251, Vol. 5, No. 8
1535-9778/06/$08.00+0     doi:10.1128/EC.00048-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Antagonism between Two Mechanisms of Antifungal Drug Resistance

James B. Anderson, Nicole Ricker, and Caroline Sirjusingh

Department of Biology, University of Toronto, 3359 Mississauga Road North, Mississauga, Ontario L5L 1C6, Canada

Received 16 February 2006/ Accepted 18 May 2006

This study tested for interaction between two independently evolved mechanisms of fluconazole resistance in Saccharomyces cerevisiae. One set of strains was from a 400-generation evolution experiment, during which the concentration of fluconazole was increased from 16 to 256 µg/ml in four increments. At 100 generations, populations became fixed for resistance mutations in either of two transcriptional regulators, PDR1 or PDR3. At 400 generations, replicate populations became fixed for another resistance mutation in UNK1, an unmapped gene further increasing resistance. Another genotype used in this study came from a population placed initially in 128 µg/ml of fluconazole; this environment selects for resistance through loss of function at ERG3, resulting in altered sterol metabolism. Mutant strains carrying PDR1r or PDR3r were crossed with the erg3r mutant strain, and the doubly mutant, haploid offspring were identified. The double-mutant strains grew less well than the parent strains at all concentrations of fluconazole tested. In genome-wide assays of gene expression, several ABC transporter genes that were overexpressed in one parent and several ERG genes that were overexpressed in the other parent were also overexpressed in the double mutants. Of the 43 genes that were consistently overexpressed in the PDR1r parents at generation 100, however, 31 were not consistently overexpressed in the double mutants. Of these 31 genes, 30 were also not consistently overexpressed after a further 300 generations of evolution in the PDR1r parent populations. The two independently evolved mechanisms of fluconazole resistance are strongly antagonistic to one another.

* Corresponding author. Mailing address: Department of Biology, University of Toronto, 3359 Mississauga Road North, Mississauga, Ontario L5L 1C6, Canada. Phone: (905) 828-5362. Fax: (905) 828-3792. E-mail: janderso{at}utm.utoronto.ca.

Eukaryotic Cell, August 2006, p. 1243-1251, Vol. 5, No. 8
1535-9778/06/$08.00+0     doi:10.1128/EC.00048-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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