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Antimicrobial Agents and Chemotherapy, October 1998, p. 2645-2649, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Mechanism of Fluconazole Resistance in Candida krusei

Alison S. Orozco,1 Lindsey M. Higginbotham,1 Christopher A. Hitchcock,2 Tanya Parkinson,2 Derek Falconer,2 Ashraf S. Ibrahim,1 Mahmoud A. Ghannoum,1,3,dagger and Scott G. Filler1,3,*

St. John's Cardiovascular Research Center, Division of Infectious Diseases, Harbor-UCLA Research and Education Institute, Torrance, California 905021; Pfizer Central Research, Sandwich, Kent, United Kingdom2; and the UCLA School of Medicine, Los Angeles, California 900243

Received 2 April 1998/Returned for modification 30 May 1998/Accepted 9 July 1998

The mechanisms of fluconazole resistance in three clinical isolates of Candida krusei were investigated. Analysis of sterols of organisms grown in the absence and presence of fluconazole demonstrated that the predominant sterol of C. krusei is ergosterol and that fluconazole inhibits 14alpha -demethylase in this organism. The 14alpha -demethylase activity in cell extracts of C. krusei was 16- to 46-fold more resistant to inhibition by fluconazole than was 14alpha -demethylase activity in cell extracts of two fluconazole-susceptible strains of Candida albicans. Comparing the carbon monoxide difference spectra of microsomes from C. krusei with those of microsomes from C. albicans indicated that the total cytochrome P-450 content of C. krusei is similar to that of C. albicans. The Soret absorption maximum in these spectra was located at 448 nm for C. krusei and at 450 nm for C. albicans. Finally, the fluconazole accumulation of two of the C. krusei isolates was similar to if not greater than that of C. albicans. Thus, there are significant qualitative differences between the 14alpha -demethylase of C. albicans and C. krusei. In addition, fluconazole resistance in these strains of C. krusei appears to be mediated predominantly by a reduced susceptibility of 14alpha -demethylase to inhibition by this drug.

* Corresponding author. Mailing address: Division of Infectious Diseases, Harbor-UCLA Research and Education Institute, 1124 West Carson St., RB-2, Torrance, CA 90502. Phone: (310) 222-6426. Fax: (310) 782-2016. E-mail: Filler{at}HUMC.EDU.

dagger Present address: Department of Dermatology, Center for Medical Mycology, Case Western Reserve University, Cleveland, OH 44106.

Antimicrobial Agents and Chemotherapy, October 1998, p. 2645-2649, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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