UPC2 is universally essential for azole antifungal resistance in Candida albicans

Erin M. Vasicek, Elizabeth L. Berkow, Stephanie A. Flowers, Katherine S. Barker, Phillip Rogers

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)933-946
Number of pages14
JournalEukaryotic Cell
Volume13
Issue number7
DOIs
StatePublished - Jan 1 2014

Fingerprint

Azoles
Candida albicans
Fluconazole
Disk Diffusion Antimicrobial Tests
Iron
Ergosterol
Mutation
Gene Regulatory Networks
Sterols
Microarray Analysis
Homeostasis
Transcription Factors
Genes

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Molecular Biology

Cite this

UPC2 is universally essential for azole antifungal resistance in Candida albicans. / Vasicek, Erin M.; Berkow, Elizabeth L.; Flowers, Stephanie A.; Barker, Katherine S.; Rogers, Phillip.

In: Eukaryotic Cell, Vol. 13, No. 7, 01.01.2014, p. 933-946.

Research output: Contribution to journalArticle

Vasicek, Erin M. ; Berkow, Elizabeth L. ; Flowers, Stephanie A. ; Barker, Katherine S. ; Rogers, Phillip. / UPC2 is universally essential for azole antifungal resistance in Candida albicans. In: Eukaryotic Cell. 2014 ; Vol. 13, No. 7. pp. 933-946.
@article{9cba68d10e404d52b8768c6bd2b325e9,
title = "UPC2 is universally essential for azole antifungal resistance in Candida albicans",
abstract = "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.",
author = "Vasicek, {Erin M.} and Berkow, {Elizabeth L.} and Flowers, {Stephanie A.} and Barker, {Katherine S.} and Phillip Rogers",
year = "2014",
month = "1",
day = "1",
doi = "10.1128/EC.00221-13",
language = "English (US)",
volume = "13",
pages = "933--946",
journal = "Eukaryotic Cell",
issn = "1535-9778",
publisher = "American Society for Microbiology",
number = "7",

}

TY - JOUR

T1 - UPC2 is universally essential for azole antifungal resistance in Candida albicans

AU - Vasicek, Erin M.

AU - Berkow, Elizabeth L.

AU - Flowers, Stephanie A.

AU - Barker, Katherine S.

AU - Rogers, Phillip

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84903648333&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903648333&partnerID=8YFLogxK

U2 - 10.1128/EC.00221-13

DO - 10.1128/EC.00221-13

M3 - Article

VL - 13

SP - 933

EP - 946

JO - Eukaryotic Cell

JF - Eukaryotic Cell

SN - 1535-9778

IS - 7

ER -