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| Status |
Public on May 24, 2014 |
| Title |
UPC2 Is universally essential for Azole antifungal resistance in Candida albicans |
| Organism |
Candida albicans |
| Experiment type |
Expression profiling by array
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| Summary |
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 upc2Δ/Δ mutant than for its azole-susceptible parent, SC5314. Moreover, the upc2Δ/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 upc2Δ/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 upc2Δ/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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| Overall design |
We examined the genome-wide gene expression profiles of the wild-type parent strain SC5314 and its upc2Δ/Δ derivative in response to fluconazole in order to identify genes whose expression in response to fluconazole is influenced by Upc2.
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| Contributor(s) |
Vasicek EM, Berkow EL, Flowers SA, Barker KS, Rogers PD |
| Citation(s) |
24659578 |
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| Submission date |
May 23, 2014 |
| Last update date |
Aug 06, 2014 |
| Contact name |
Erin Vasicek |
| E-mail(s) |
[email protected]
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| Organization name |
University of Tennessee Health Science Center
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| Street address |
881 Madison Ave
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| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38163 |
| Country |
USA |
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| Platforms (1) |
| GPL6808 |
[CAN07a520619F] Candida albicans 11-mer Affymetrix 10K array version1 |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA248441 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE57929_RAW.tar |
10.9 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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