The Transcription Factor Ndt80 Does Not Contribute to Mrr1-, Tac1-, and Upc2-Mediated Fluconazole Resistance in Candida albicans

Sasse, Christoph; Schillig, Rebecca; Dierolf, Franziska; Weyler, Michael; Schneider, Sabrina; Mogavero, Selene; Rogers, P. David; Morschhäuser, Joachim

doi:10.1371/journal.pone.0025623

Cited by 61Antifungal resistance and susceptibilityFungal and yeast genetics researchDrug Transport and Resistance Mechanisms

The Transcription Factor Ndt80 Does Not Contribute to Mrr1-, Tac1-, and Upc2-Mediated Fluconazole Resistance in Candida albicans

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Sasse, Christoph, Schillig, Rebecca, Dierolf, Franziska, Weyler, Michael, Schneider, Sabrina, Mogavero, Selene, Rogers, P. David, Morschhäuser, Joachim·2011·PLoS ONE

DOI 10.1371/journal.pone.0025623PMC PMC3181345

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Abstract

The pathogenic yeast Candida albicans can develop resistance to the widely used antifungal agent fluconazole, which inhibits ergosterol biosynthesis, by the overexpression of genes encoding multidrug efflux pumps or ergosterol biosynthesis enzymes. Zinc cluster transcription factors play a central role in the transcriptional regulation of drug resistance. Mrr1 regulates the expression of the major facilitator MDR1, Tac1 controls the expression of the ABC transporters CDR1 and CDR2, and Upc2 regulates ergosterol biosynthesis (ERG) genes. Gain-of-function mutations in these transcription factors result in constitutive overexpression of their target genes and are responsible for fluconazole resistance in many clinical C. albicans isolates. The transcription factor Ndt80 contributes to the drug-induced upregulation of CDR1 and ERG genes and also binds to the MDR1 and CDR2 promoters, suggesting that it is an important component of all major transcriptional mechanisms of fluconazole resistance. However, we found that Ndt80 is not required for the induction of MDR1 and CDR2 expression by inducing chemicals. CDR2 was even partially derepressed in ndt80Δ mutants, indicating that Ndt80 is a repressor of CDR2 expression. Hyperactive forms of Mrr1, Tac1, and Upc2 promoted overexpression of MDR1, CDR1/CDR2, and ERG11, respectively, with the same efficiency in the presence and absence of Ndt80. Mrr1- and Tac1-mediated fluconazole resistance was even slightly enhanced in ndt80Δ mutants compared to wild-type cells. These results demonstrate that Ndt80 is dispensable for the constitutive overexpression of Mrr1, Tac1, and Upc2 target genes and the increased fluconazole resistance of strains that have acquired activating mutations in these transcription factors.

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Hyperactive forms of Mrr1p, Tac1p, and Upc2p up-regulate their target genes independent of Ndt80p and thereby mediate drug resistance in clinical strains.
“This result is attributed to hyperactive forms of Mrr1p, Tac1p, and Upc2p, which up-regulate their target genes independent of Ndt80p and thereby mediate drug resistance in clinical strains.”
From The synthesis, regulation, and functions of sterols inCandida albicans: Well-known but still lots to learn (2016) · cites this paper as [60]
Multiple gain-of-function mutations in Tac1 leading to increased expression of Cdr1 and Cdr2 efflux transporters have been described.
“Since then, multiple gain-of-function mutations in Tac1 (Figure 2a) leading to increased expression of the Cdr1 and Cdr2 efflux transporters have been described.81 , 85–87”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [86]

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The transcription factor Ndt80 does not contribute to
Sasse, C., Schillig, R., Dierolf, F., Weyler, M., Schneider, S., Mogavero, S., & Rogers, P. D. (2016)
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MOLECULAR MECHANISMS OF DRUG RESISTANCE IN CANDIDA ALBICANS: ROLE OF TRANSCRIPTION FACTORS MCM1 AND ADA2
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Authors: Sasse, C., Schillig, R., Dierolf, F., Weyler, M., Schneider, S., Mogavero, S., Rogers, P. D., & Morschhäuser, J.
Affiliations: University of Würzburg (DE)
University of Pisa (IT)
University of Tennessee Health Science Center (US)
Corresponding author: Morschhäuser, Joachim
ORCID: Sasse, Christoph
Mogavero, Selene
Rogers, P. David
Morschhäuser, Joachim
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2011-09-27
Volume: 6
Issue: 9
Pages: e25623
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0025623
PMC: PMC3181345
OpenAlex: W2129494864
Cited by: 61
References: 36
Citations by year: 2026: 3 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 9 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 3 · 2014: 9 · 2013: 5 · 2012: 4
FWCI: 3.88
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion, cc-by)
Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
Funders: Deutsche Forschungsgemeinschaft (SFB 630, MO 846/3)
Università di Pisa
National Institutes of Health (AI058145)
National Institute of Allergy and Infectious Diseases (R01AI058145, AI058145, R21AI058145)
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords: Ndt80, fluconazole resistance, Candida albicans, MRR1, TAC1, UPC2, zinc cluster transcription factors, MDR1, CDR1, CDR2, ERG11, ergosterol biosynthesis, multidrug efflux pumps, transcriptional regulation, drug resistance, gain-of-function mutations
MeSH terms: Alleles, Candida albicans, DNA-Binding Proteins, Fungal Proteins, Transcription Factors, Fluconazole, Up-Regulation, Gene Expression Regulation, Fungal, Drug Resistance, Fungal

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The Transcription Factor Ndt80 Does Not Contribute to Mrr1-, Tac1-, and Upc2-Mediated Fluconazole Resistance in Candida albicans

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