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Journal of Bacteriology, July 1999, p. 4041-4049, Vol. 181, No. 13
0021-9193/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Specific Chromosome Alterations in Fluconazole-Resistant Mutants of Candida albicans

Valentina Perepnikhatka,1 Frank J. Fischer,2 Masakazu Niimi,2 Rachel A. Baker,2 Richard D. Cannon,2 Ying-Kai Wang,1 Fred Sherman,1 and Elena Rustchenko1,*

Department of Biochemistry and Biophysics, University of Rochester Medical School, Rochester, New York 14642,1 and Department of Oral Sciences and Orthodontics, University of Otago, Dunedin, New Zealand2

Received 3 February 1999/Accepted 23 April 1999

The exposure of Candida albicans to fluconazole resulted in the nondisjunction of two specific chromosomes in 17 drug-resistant mutants, each obtained by an independent mutational event. The chromosomal changes occurred at high frequencies and were related to the duration of the drug exposure. The loss of one homologue of chromosome 4 occurred after incubation on a fluconazole medium for 7 days. A second change, the gain of one copy of chromosome 3, was observed after exposure for 35 or 40 days. We found that the mRNA levels of ERG11, CDR1, CDR2, and MDR1, the candidate fluconazole resistance genes, remained either the same or were diminished. The lack of overexpression of putative drug pumps or the drug target indicated that some other mechanism(s) may be operating. The fluconazole resistance phenotype, electrophoretic karyotypes, and transcript levels of mutants were stable after growth for 112 generations in the absence of fluconazole. This is the first report to demonstrate that resistance to fluconazole can be dependent on chromosomal nondisjunction. Furthermore, we suggest that a low-level resistance to fluconazole arising during the early stages of clinical treatment may occur by this mechanism. These results support our earlier hypothesis that changes in C. albicans chromosome number is a common means to control a resource of potentially beneficial genes that are related to important cellular functions.

* Corresponding author. Mailing address: Department of Biochemistry and Biophysics, P.O. Box 712, University of Rochester Medical School, Rochester, NY 14642. Phone: (716) 275-6710. Fax: (716) 271-2683. E-mail: elena_bulgac{at}urmc.rochester.edu.

Journal of Bacteriology, July 1999, p. 4041-4049, Vol. 181, No. 13
0021-9193/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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