The fungicide fludioxonil antagonizes fluconazole activity in the human fungal pathogen Candida albicans.
The fungicide fludioxonil is widely used in agriculture. Residua of this fungicide are occasionally detected in fruits and can therefore be ingested by humans. The human fungal pathogen Candida albicans expresses the target of fludioxonil, Nik1p, a type III histidine kinase involved in stress response. Inhibition of yeast and hyphae growth was hardly observable after treatment of C. albicans SC5314 with fludioxonil. As a side effect, however, we observed a concentration-dependent induction of the expression of the genes CDR1 and CDR2, encoding ATP-binding cassette (ABC) transporters. This was independent of the presence of the target of fludioxonil as induction was also observed in a Δnik1 deletion mutant. Deletion of the CDR1 gene aggravated the inhibition of germ tube formation by fludioxonil, indicating that, in the wild-type, the fungicide was discharged from the cell by Cdr1p. Cdr1p is also known as a resistance factor of C. albicans against the commonly used antimycotic fluconazole. Thus, the effect of concurrent exposure to fludioxonil and known cargoes of ABC transporters on their extrusion and the growth of C. albicans was examined. Pre-incubation with fludioxonil decreased the export rate of rhodamine 6G. The resistance to fluconazole was increased by fludioxonil, independently of Nik1p. Therefore, exposure of C. albicans to fludioxonil may lead to increased resistance to fluconazole treatment.
Biological Systems Analysis, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Anna
A
Buschart
Biological Systems Analysis, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Anna
A
Burakowska
Biological Systems Analysis, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Ursula
U
Bilitewski
D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002177:Candidiasis / Q000188:drug therapy; D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000378:metabolism / Q000494:pharmacology*; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D005656:Fungal Proteins / Q000096:biosynthesis / Q000235:genetics*; D005659:Fungicides, Industrial / Q000494:pharmacology; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D000071677:Histidine Kinase; D006801:Humans; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D011494:Protein Kinases / Q000187:drug effects; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D012235:Rhodamines / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; C094693:CDR1 protein, Candida albicans; D004149:Dioxoles; D005656:Fungal Proteins; D005659:Fungicides, Industrial; D026901:Membrane Transport Proteins; D011758:Pyrroles; D012235:Rhodamines; C026188:rhodamine 6G; D015725:Fluconazole; D011494:Protein Kinases; D000071677:Histidine Kinase; C108339:fludioxonil