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Journal of Bacteriology, March 2000, p. 1515-1522, Vol. 182, No. 6
0021-9193/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Evolution of Drug Resistance in Experimental Populations of Candida albicans

Leah E. Cowen,1,* Dominique Sanglard,2 David Calabrese,2 Caroline Sirjusingh,1 James B. Anderson,1 and Linda M. Kohn1

Department of Botany, University of Toronto, Mississauga, Ontario, Canada L5L 1C6,1 and Institute of Microbiology, University Hospital, 1011 Lausanne, Switzerland2

Received 16 September 1999/Accepted 21 December 1999

Adaptation to inhibitory concentrations of the antifungal agent fluconazole was monitored in replicated experimental populations founded from a single, drug-sensitive cell of the yeast Candida albicans and reared over 330 generations. The concentration of fluconazole was maintained at twice the MIC in six populations; no fluconazole was added to another six populations. All six replicate populations grown with fluconazole adapted to the presence of drug as indicated by an increase in MIC; none of the six populations grown without fluconazole showed any change in MIC. In all populations evolved with drug, increased fluconazole resistance was accompanied by increased resistance to ketoconazole and itraconazole; these populations contained ergosterol in their cell membranes and were amphotericin sensitive. The increase in fluconazole MIC in the six populations evolved with drug followed different trajectories, and these populations achieved different levels of resistance, with distinct overexpression patterns of four genes involved in azole resistance: the ATP-binding cassette transporter genes, CDR1 and CDR2; the gene encoding the target enzyme of the azoles in the ergosterol biosynthetic pathway, ERG11; and the major facilitator gene, MDR1. Selective sweeps in these populations were accompanied by additional genomic changes with no known relationship to drug resistance: loss of heterozygosity in two of the five marker genes assayed and alterations in DNA fingerprints and electrophoretic karyotypes. These results show that chance, in the form of mutations that confer an adaptive advantage, is a determinant in the evolution of azole drug resistance in experimental populations of C. albicans.

* Corresponding author. Mailing address: Department of Botany, University of Toronto at Mississauga, 3359 Mississauga Rd. North, Mississauga, Ontario, Canada L5L 1C6. Phone: (905) 828-5338. Fax: (905) 828-3792. E-mail: lcowen{at}credit.erin.utoronto.ca.

Journal of Bacteriology, March 2000, p. 1515-1522, Vol. 182, No. 6
0021-9193/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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