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Antimicrobial Agents and Chemotherapy, February 2001, p. 420-427, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.420-427.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Dynamic and Heterogeneous Mutations to Fluconazole Resistance in Cryptococcus neoformans

Jianping Xu,* Chiatogu Onyewu, Heather J. Yoell, Rabia Y. Ali, Rytas J. Vilgalys, and Thomas G. Mitchell

Department of Microbiology, Duke University Medical Center, Durham, North Carolina 27710

Received 14 July 2000/Returned for modification 29 August 2000/Accepted 30 October 2000

Infections with the human pathogenic basidiomycetous yeast Cryptococcus neoformans are often treated with fluconazole. Resistance to this antifungal agent has been reported. This study investigated the patterns of mutation to fluconazole resistance in C. neoformans in vitro. The MIC of fluconazole was measured for 21 strains of C. neoformans. The MICs for these 21 strains differed (0.25 to 4.0 µg/ml), but the strains were selected for this study because they exhibited no growth on plates of yeast morphology agar (YMA) containing 8 µg of fluconazole per ml. To determine their mutation rates, six independent cultures from a single original colony were established for each of the 21 strains. Each culture was then spread densely on a YMA plate with 8 µg of fluconazole per ml. A random set of putative mutants was subcultured, and the MIC of fluconazole was determined for each mutant. The 21 strains evinced significant heterogeneity in their mutation rates. The MICs of the putative mutants ranged widely, from their original MIC to 64 µg of fluconazole per ml. However, for this set of 21 strains, there was no significant correlation between the original MIC for a strain and the mutation rate of that strain; the MIC for the mutant could not be predicted from the original MIC. These results suggest that dynamic and heterogeneous mutational processes are involved in generating fluconazole resistance in C. neoformans.

* Corresponding author. Present address: Department of Biology, McMaster University, Hamilton, Ontario, Canada L8S 4K1. Phone: 1-905-525-9140 ext. 27934. Fax: 1-905-522-6066. E-mail: jpxu{at}mcmaster.ca.

Antimicrobial Agents and Chemotherapy, February 2001, p. 420-427, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.420-427.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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