Mutations in the multi‐drug resistance regulator MRR1 , followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole‐resistant Candida albicans strains

Dunkel, Nico; Blaß, Julia; Rogers, P. David; Morschhäuser, Joachim

doi:10.1111/j.1365-2958.2008.06309.x

Cited by 278Antifungal resistance and susceptibilityFungal and yeast genetics researchDrug Transport and Resistance Mechanisms

Mutations in the multi‐drug resistance regulator MRR1 , followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole‐resistant Candida albicans strains

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Dunkel, Nico, Blaß, Julia, Rogers, P. David, Morschhäuser, Joachim·2008·Molecular Microbiology

DOI 10.1111/j.1365-2958.2008.06309.xPMC PMC2678921

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Abstract

Summary: Overexpression of the MDR1 gene, encoding a multi‐drug efflux pump of the major facilitator superfamily, is a major cause of resistance to the widely used antifungal agent fluconazole and other toxic substances in the fungal pathogen Candida albicans . We found that all tested clinical and in vitro generated C. albicans strains that had become fluconazole‐resistant by constitutive MDR1 upregulation contained mutations in the MRR1 gene, which encodes a transcription factor that controls MDR1 expression. Introduction of the mutated alleles into a drug‐susceptible C. albicans strain resulted in activation of the MDR1 promoter and multi‐drug resistance, confirming that the amino acid substitutions in Mrr1p were gain‐of‐function mutations that rendered the transcription factor constitutively active. The majority of the MDR1 overexpressing strains had become homozygous for the mutated MRR1 alleles, demonstrating that the increased resistance level conferred by two gain‐of‐function alleles provides sufficient advantage to select for the loss of heterozygosity in the presence of fluconazole both in vitro and within the human host during therapy. Loss of heterozygosity usually occurred by mitotic recombination between the two chromosome 3 homologues on which MRR1 is located, but evidence for complete loss of one chromosome and duplication of the chromosome containing the mutated MRR1 allele was also obtained in two in vitro generated fluconazole‐resistant strains. These results demonstrate that gain‐of‐function mutations in MRR1 are the major, if not the sole, mechanism of MDR1 overexpression in fluconazole‐resistant strains and that this transcription factor plays a central role in the development of drug resistance in C. albicans .

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MRR1GOF mutations induce drug efflux gene expression and are commonly found in fluconazole-resistant C. albicans clinical isolates.
“MRR1GOF mutations induce drug efflux gene expression and are commonly found in fluconazole-resistant C. albicans clinical isolates (1, 2, 17, 18).”
From Candida albicans Swi/Snf and Mediator Complexes Differentially Regulate Mrr1-Induced MDR1 Expression and Fluconazole Resistance (2017) · cites this paper as [18]
The Discussion reports that gain-of-function MRR1 mutations cause upregulation of the MDR1 efflux pump in all nine clinical isolates investigated. Those isolates were specifically MDR1-overexpressing and fluconazole-resistant; the paper does not establish that the mutations are common among fluconazole-resistant clinical isolates generally. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Drug efflux pumps Cdr1, Cdr2, and Mdr1 play a crucial role in mediating fluconazole resistance in C. albicans, and are often upregulated in response to fluconazole exposure.
“Drug efflux pumps, such as Cdr1, Cdr2, and Mdr1, also play a crucial role in mediating fluconazole resistance in C. albicans, as these are often upregulated in response to fluconazole exposure (8, 9).”
From Candida albicans enhances iron uptake to maintain fluconazole resistance (2025) · cites this paper as [9]
The Introduction (page unavailable) identifies Cdr1, Cdr2, and Mdr1 as efflux pumps whose overexpression contributes to fluconazole resistance in many clinical isolates. It describes constitutive overexpression in resistant strains and induction by steroids or certain other chemicals, but does not establish that these pumps are often upregulated in response to fluconazole exposure. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Fluconazole-resistant isolates that overexpress MDR1 have become homozygous for the mutated MRR1 allele and work in a semidominant fashion if expressed with a wild-type allele.
“Fluconazole-resistant isolates that overexpress MDR1 have become homozygous for the mutated MRR1 allele and work in a semidominant fashion if expressed with a wild-type allele (6).”
From Gain-of-Function Mutations in UPC2 Are a Frequent Cause of ERG11 Upregulation in Azole-Resistant Clinical Isolates of Candida albicans (2012) · cites this paper as [6]
The Discussion (page unavailable) says gain-of-function MRR1 alleles can activate MDR1 in the presence of a wild-type allele, supporting the semidominant description. It also says most—not all—MDR1-overexpressing, fluconazole-resistant strains became homozygous for a mutated MRR1 allele (11 of 14 analysed); the unqualified claim overstates that finding. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Regulation of efflux protein expression can occur by gain-of-function mutations in the transcription factors Tac1p and Mrr1p that are associated with greater Cdr1p/Cdr2p or Mdr1p expression, respectively, in resistant cells.
“Regulation of efflux protein expression can also occur by gain-of-function mutations in the transcription factors Tac1p and Mrr1p that are associated with greater Cdr1p/Cdr2p or Mdr1p expression, respectively, in resistant cells (5, 6).”
From Azole Susceptibility and Transcriptome Profiling in Candida albicans Mitochondrial Electron Transport Chain Complex I Mutants (2013) · cites this paper as [6]
Triazole resistance occurs as a result of the upregulation of multidrug efflux transporters of two gene families, the ABC transporters and the major facilitator gene superfamily (MFS).
“Triazole resistance also occurs as a result of the upregulation of multidrug efflux transporters of two gene families, the ABC (ATP-binding cassette) transporters and the major facilitator gene superfamily (MFS).”
From Azole Susceptibility and Transcriptome Profiling in Candida albicans Mitochondrial Electron Transport Chain Complex I Mutants (2013) · cites this paper as [6]

Other genes, including ERG11, CDR1, and CDR2, were largely unaffected in MRR1GOF mutant strains in the ssn3 null background.
“Other genes, including ERG11, CDR1, and CDR2, whose overexpression can lead to fluconazole resistance (2, 18, 32), were also found to be largely unaffected in MRR1GOF mutant strains in the ssn3 null background (Fig. S8).”
From Candida albicans Swi/Snf and Mediator Complexes Differentially Regulate Mrr1-Induced MDR1 Expression and Fluconazole Resistance (2017) · cites this paper as [18]
Mrr1 is the regulator of the major facilitator superfamily transporter Mdr1 in azole-resistant isolates, and specific mutations in this transcriptional regulator result in its constitutive activation, leading to overexpression of Mdr1.
“Likewise, Mrr1 has been identified as the regulator of the major facilitator superfamily (MFS) transporter Mdr1 in azole-resistant isolates, and specific mutations in this transcriptional regulator result in its constitutive activation, leading to the overexpression of Mdr1 (6, 22).”
From Gain-of-Function Mutations in UPC2 Are a Frequent Cause of ERG11 Upregulation in Azole-Resistant Clinical Isolates of Candida albicans (2012) · cites this paper as [6]
In C. albicans genome studies, serial isolates allowed the identification of alterations that may have contributed to drug resistance over the treatment course, including segmental aneuploidies, loss of heterozygosity, and gene-level alterations.
“In genome studies of the other major yeast pathogen, C. albicans, serial isolates allowed the identification of several alterations that may have contributed to drug resistance over the treatment course, including segmental aneuploidies (Selmecki et al., 2006), loss of heterozygosity (LOH) in large parts of the chromosomes (Dunkel et al., 2008), and alterations at the gene level.”
From Genome Comparisons of Candida glabrata Serial Clinical Isolates Reveal Patterns of Genetic Variation in Infecting Clonal Populations (2019) · cites this paper as Dunkel et al., 2008
Increased efflux of the drug from cells by ABC transporters (encoded by CDR1 and CDR2) or by the major facilitator superfamily efflux pump (encoded by MDR1) reduces the effective intracellular drug concentration.
“Second, increased efflux of the drug from cells by ABC transporters (encoded by CDR1 and CDR2) (Coste et al., 2006) or by the major facilitator superfamily efflux pump (encoded by MDR1) (Dunkel et al., 2008) reduces the effective intracellular drug concentration.”
From The evolution of drug resistance in clinical isolates of Candida albicans. (2015) · cites this paper as Dunkel et al., 2008
Gain-of-function mutations in TAC1 result in constitutive overexpression of both CDR1 and CDR2, while activating mutations in MRR1 are responsible for upregulation of MDR1.
“Specifically, gain-of-function mutations in the transcriptional activator gene, TAC1, result in constitutive overexpression of both CDR1 and CDR2, while activating mutations in MRR1 are responsible for the upregulation of MDR152,53.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [53]
Multiple amino acid substitutions in Mrr1 originating from both human clinical isolates and in vitro-generated strains are gain-of-function mutations driving constitutive MDR1 expression.
“Indeed, multiple amino acid substitutions in Mrr1 originating from both human clinical isolates and in vitro-generated strains have been shown to be gain-of-function mutations driving constitutive MDR1 expression (Figure 2b).104”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [104]
For both TAC1 and MRR1, loss of heterozygosity was responsible in some clinical isolates for homozygous gain-of-function mutations conferring increased efflux pump expression and azole resistance.
“it has been shown for both TAC1 and MRR1 that loss of heterozygosity was responsible in some clinical isolates for homozygous gain-of-function mutations conferring increased efflux pump expression and azole resistance.”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [104]

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“Likewise, Mrr1 has been identified as the regulator of the major facilitator superfamily (MFS) transporter Mdr1 in azole-resistant isolates, and specific mutations in this transcriptional regulator result in its constitutive activation, leading to the overexpression of Mdr1 (6, 22).”
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Authors: Dunkel, N., Blaß, J., Rogers, P. D., & Morschhäuser, J.
Affiliations: University of Würzburg (DE)
University of Tennessee Health Science Center (US)
Corresponding author: Morschhäuser, Joachim
ORCID: Rogers, P. David
Morschhäuser, Joachim
Venue: Molecular Microbiology
Publisher: Wiley
Published: 2008-07-23
Volume: 69
Issue: 4
Pages: 827-840
ISSN: 0950-382X (ISSN-L)
1365-2958
DOI: 10.1111/j.1365-2958.2008.06309.x
PMC: PMC2678921
OpenAlex: W1976673671
Cited by: 278
References: 36
Citations by year: 2026: 14 · 2025: 18 · 2024: 13 · 2023: 21 · 2022: 15 · 2021: 11 · 2020: 19 · 2019: 13 · 2018: 11 · 2017: 27 · 2016: 12 · 2015: 12 · 2014: 15 · 2013: 11 · 2012: 13
FWCI: 11.20
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Molecular Microbiology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Deutsche Forschungsgemeinschaft (SFB 630)
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: MRR1, MDR1, Candida albicans, fluconazole resistance, loss of heterozygosity, gain-of-function mutations, transcription factors, major facilitator superfamily, mitotic recombination, chromosome 3, antifungal resistance, transcriptional regulation
MeSH terms: Alleles, Antifungal Agents, Base Sequence, Candida albicans, Fungal Proteins, Genes, Regulator, Molecular Sequence Data, Mutation, Promoter Regions, Genetic, Recombination, Genetic, Transcription Factors, Transcriptional Activation, Fluconazole, Up-Regulation, Gene Expression Regulation, Fungal, Protein Structure, Tertiary, Loss of Heterozygosity, ATP Binding Cassette Transporter, Subfamily B, Member 1, Drug Resistance, Multiple, Fungal

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Mutations in the multi‐drug resistance regulator MRR1 , followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole‐resistant Candida albicans strains

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