Affiliation:
1. Institut für Molekulare Infektionsbiologie, Universität Würzburg, Röntgenring 11, D-97070 Würzburg, Germany
2. Institute of Microbiology, University Hospital Lausanne, Lausanne, Switzerland
Abstract
ABSTRACT
Overexpression of
MDR1
, which encodes a membrane transport protein of the major facilitator superfamily, is one mechanism by which the human fungal pathogen
Candida albicans
can develop increased resistance to the antifungal drug fluconazole and other toxic compounds. In clinical
C. albicans
isolates, constitutive
MDR1
overexpression is accompanied by the upregulation of other genes, but it is not known if these additional alterations are required for Mdr1p function and drug resistance. To investigate whether
MDR1
overexpression is sufficient to confer a drug-resistant phenotype in
C. albicans
, we expressed the
MDR1
gene from the strong
ADH1
promoter in
C. albicans
laboratory strains that did not express the endogenous
MDR1
gene as well as in a fluconazole-resistant clinical
C. albicans
isolate in which the endogenous
MDR1
alleles had been deleted and in a matched fluconazole-susceptible isolate from the same patient. Forced
MDR1
overexpression resulted in increased resistance to the putative Mdr1p substrates cerulenin and brefeldin A, and this resistance did not depend on the additional alterations which occurred during drug resistance development in the clinical isolates. In contrast, artificial expression of the
MDR1
gene from the
ADH1
promoter did not enhance or only slightly enhanced fluconazole resistance, presumably because Mdr1p expression levels in the transformants were considerably lower than those observed in the fluconazole-resistant clinical isolate. These results demonstrate that
MDR1
overexpression in
C. albicans
is sufficient to confer resistance to some toxic compounds that are substrates of this efflux pump but that the degree of resistance depends on the Mdr1p expression level.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
78 articles.
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