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Antimicrobial Agents and Chemotherapy, May 2009, p. 1931-1936, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01315-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Gene Expression and Evolution of Antifungal Drug Resistance{triangledown} ,{dagger}

James B. Anderson,* Caroline Sirjusingh, Nazia Syed, and Shantelle Lafayette

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

Received 1 October 2008/ Returned for modification 14 December 2008/ Accepted 24 February 2009

Permanent changes in gene expression result from certain forms of antifungal resistance. In this study, we asked whether any changes in gene expression are required for the evolution of a drug-resistant phenotype in populations. We examined the changes in gene expression resulting from the evolution of resistance in experimental populations of the yeast Saccharomyces cerevisiae with two antifungal drugs, fluconazole (FLC) in a previous study and amphotericin B (AmB) in this study, in which five populations were subjected to increasing concentrations of AmB, from 0.25 to 128 µg/ml in twofold increments. Six genes, YGR035C, YOR1, ICT1, GRE2, PDR16, and YPLO88W, were consistently overexpressed with resistance to AmB reported here and with resistance to FLC involving a mechanism of increased efflux reported previously. We then asked if the deletion of these genes impaired the ability of populations to evolve resistance to FLC over 108 generations of asexual reproduction in 32 and 128 µg/ml FLC, the same conditions under which FLC-resistant types evolved originally. For each of three deletion strains, YOR1, ICT1, and PDR16 strains, extinctions occurred in one of two replicate populations growing in 128 µg/ml FLC. Each of these three deletion strains was mixed 1:1 with a marked version of the wild type to measure the relative ability of the deletion strain to adapt over 108 generations. In these assays, only the PDR16 deletion strain consistently became extinct both at 32 and at 128 µg/ml FLC. The deletion of PDR16 reduces the capacity of a population to evolve to resistance to FLC.

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

{triangledown} Published ahead of print on 9 March 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, May 2009, p. 1931-1936, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.01315-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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