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Antimicrobial Agents and Chemotherapy, December 1998, p. 3065-3072, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Multiple Molecular Mechanisms Contribute to a Stepwise Development of Fluconazole Resistance in Clinical Candida albicans Strains

Renate Franz,1 Steven L. Kelly,2 David C. Lamb,2 Diane E. Kelly,2 Markus Ruhnke,3 and Joachim Morschhäuser1,*

Zentrum für Infektionsforschung, Universität Würzburg, D-97070 Würzburg,1 and Charité Campus Virchow-Klinikum, Humboldt-Universität Berlin, D-13353 Berlin,3 Germany, and Institute of Biological Sciences, University of Wales---Aberystwyth, Aberystwyth, Wales, SY23 3DA, United Kingdom2

Received 29 September 1997/Returned for modification 31 October 1997/Accepted 11 September 1998

From each of two AIDS patients with oropharyngeal candidiasis, five Candida albicans isolates from recurrent episodes of infection which became gradually resistant against fluconazole during antimycotic treatment were analyzed for molecular changes responsible for drug resistance. In both patients, a single C. albicans strain was responsible for the recurrent infections, but the CARE-2 fingerprint pattern of the isolates exhibited minor genetic alterations, indicating that microevolution of the strains took place during fluconazole therapy. In the isolates from patient 1, enhanced mRNA levels of the MDR1 gene, encoding a multiple drug resistance protein from the superfamily of major facilitators, and constitutive high expression of the ERG11 gene, coding for the drug target enzyme sterol 14alpha -demethylase, correlated with a stepwise development of fluconazole resistance. The resistant strains exhibited reduced accumulation of fluconazole and, for the last in the series, a slight increase in drug needed to inhibit sterol 14alpha -demethylation in vitro. In the isolates from patient 2, increased MDR1 mRNA levels and the change from heterozygosity to homozygosity for a mutant form of the ERG11 gene correlated with continuously decreased drug susceptibility. In this series, reduced drug accumulation and increased resistance in the target enzyme activity, sterol 14alpha -demethylase, were observed. These results demonstrate that different molecular mechanisms contribute to a gradual development of fluconazole resistance in C. albicans.

* Corresponding author. Mailing address: Zentrum für Infektionsforschung, Universität Würzburg, Röntgenring 11, D-97070 Würzburg, Germany. Phone: 49-931-31 21 52. Fax: 49-931-31 25 78. E-mail: joachim.morschhaeuser{at}mail.uni-wuerzburg.de.

Antimicrobial Agents and Chemotherapy, December 1998, p. 3065-3072, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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  • Asai, K., Tsuchimori, N., Okonogi, K., Perfect, J. R., Gotoh, O., Yoshida, Y. (1999). Formation of Azole-Resistant Candida albicans by Mutation of Sterol 14-Demethylase P450. Antimicrob. Agents Chemother. 43: 1163-1169 [Abstract] [Full Text]  


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