UPC2 Is Universally Essential for Azole Antifungal Resistance in Candida albicans
In: Eukaryotic Cell, Jg. 13 (2014-07-01), S. 933-946
Online
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Zugriff:
In Candida albicans , the transcription factor Upc2 is central to the regulation of ergosterol biosynthesis. UPC2 -activating mutations contribute to azole resistance, whereas disruption increases azole susceptibility. In the present study, we investigated the relationship of UPC2 to fluconazole susceptibility, particularly in azole-resistant strains. In addition to the reduced fluconazole MIC previously observed with UPC2 disruption, we observed a lower minimum fungicidal concentration (MFC) for a upc2 Δ/Δ mutant than for its azole-susceptible parent, SC5314. Moreover, the upc2 Δ/Δ mutant was unable to grow on a solid medium containing 10 μg/ml fluconazole and exhibited increased susceptibility and a clear zone of inhibition by Etest. Time-kill analysis showed higher fungistatic activity against the upc2 Δ/Δ mutant than against SC5314. UPC2 disruption in strains carrying specific resistance mutations also resulted in reduced MICs and MFCs. UPC2 disruption in a highly azole resistant clinical isolate containing multiple resistance mechanisms likewise resulted in a reduced MIC and MFC. This mutant was unable to grow on a solid medium containing 10 μg/ml fluconazole and exhibited increased susceptibility and a clear zone of inhibition by Etest. Time-kill analysis showed increased fungistatic activity against the upc2 Δ/Δ mutant in the resistant background. Microarray analysis showed attenuated induction by fluconazole of genes involved in sterol biosynthesis, iron transport, or iron homeostasis in the absence of UPC2 . Taken together, these data demonstrate that the UPC2 transcriptional network is universally essential for azole resistance in C. albicans and represents an attractive target for enhancing azole antifungal activity.
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UPC2 Is Universally Essential for Azole Antifungal Resistance in Candida albicans
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Autor/in / Beteiligte Person: | P. David Rogers ; Berkow, Elizabeth L. ; Flowers, Stephanie A. ; Barker, Katherine S. ; Vasicek, Erin M. |
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Zeitschrift: | Eukaryotic Cell, Jg. 13 (2014-07-01), S. 933-946 |
Veröffentlichung: | American Society for Microbiology, 2014 |
Medientyp: | unknown |
ISSN: | 1535-9786 (print) ; 1535-9778 (print) |
DOI: | 10.1128/ec.00221-13 |
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