ArticleAntimicrobial agents and chemotherapy2008
Gain-of-function mutations in the transcription factor MRR1 are responsible for overexpression of the MDR1 efflux pump in fluconazole-resistant Candida dubliniensis strains.
Article in Antimicrobial agents and chemotherapy, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed.
- Micafungin exposure drives multidrug resistance inbioRxiv : the preprint server for biology · 2026Article
- The emerging pathogen Candida auris: host interactions and disease drivers.Journal of biomedical science · 2026Review
- Adaptation of Candida albicans to specific host environments by gain-of-function mutations in transcription factors.PLoS pathogens · 2024Review
- Hsp90-Mediated Multi-Drug Resistance in DNA Polymerase-Defective Strains ofJournal of fungi (Basel, Switzerland) · 2024Article
- Review
- Clorgyline Analogs Synergize with Azoles against Drug Efflux inJournal of fungi (Basel, Switzerland) · 2023Article
- Review
- Transcriptional Response of Candida auris to the Mrr1 Inducers Methylglyoxal and Benomyl.mSphere · 2022Article
- Balancing Positive and Negative Selection:mBio · 2021Article
- Mrr1 regulation of methylglyoxal catabolism and methylglyoxal-induced fluconazole resistance in Candida lusitaniae.Molecular microbiology · 2021Article
- Interaction of Styrylpyridinium Compound with PathogenicMicroorganisms · 2020Article
- Expandable and reversible copy number amplification drives rapid adaptation to antifungal drugs.eLife · 2020Article
- Review
- Article
- An acquired mechanism of antifungal drug resistance simultaneously enables Candida albicans to escape from intrinsic host defenses.PLoS pathogens · 2017Article
- Competitive Fitness of Fluconazole-Resistant Clinical Candida albicans Strains.Antimicrobial agents and chemotherapy · 2017Article
- The synthesis, regulation, and functions of sterols in Candida albicans: Well-known but still lots to learn.Virulence · 2016Review
- The development of fluconazole resistance in Candida albicans - an example of microevolution of a fungal pathogen.Journal of microbiology (Seoul, Korea) · 2016Review
- Fluconazole and Voriconazole Resistance in Candida parapsilosis Is Conferred by Gain-of-Function Mutations in MRR1 Transcription Factor Gene.Antimicrobial agents and chemotherapy · 2015Article
- Development of fluconazole resistance in a series of Candida parapsilosis isolates from a persistent candidemia patient with prolonged antifungal therapy.BMC infectious diseases · 2015Article
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Abstract
Candida dubliniensis, a yeast that is closely related to Candida albicans, can rapidly develop resistance to the commonly used antifungal agent fluconazole in vitro and in vivo during antimycotic therapy. Fluconazole resistance in C. dubliniensis is usually caused by constitutive overexpression of the MDR1 gene, which encodes a multidrug efflux pump of the major facilitator superfamily. The zinc cluster transcription factor Mrr1p has recently been shown to control MDR1 expression in C. albicans in response to inducing stimuli, and gain-of-function mutations in the MRR1 gene result in constitutive upregulation of the MDR1 efflux pump. We identified a gene with a high degree of similarity to C. albicans MRR1 (CaMRR1) in the C. dubliniensis genome sequence. When C. dubliniensis MRR1 (CdMRR1) was expressed in C. albicans mrr1Delta mutants, it restored benomyl-inducible MDR1 expression, demonstrating that CdMRR1 is the ortholog of CaMRR1. To investigate whether MDR1 overexpression in C. dubliniensis is caused by mutations in MRR1, we sequenced the MRR1 alleles from a fluconazole-resistant, clinical C. dubliniensis isolate and a matched, fluconazole-susceptible isolate from the same patient as well as those from four in vitro-generated, fluconazole-resistant C. dubliniensis strains derived from two different C. dubliniensis isolates. We found that all five resistant strains contained single nucleotide substitutions or small in-frame deletions that resulted in amino acid changes in Mrr1p. Expression of these mutated alleles in C. albicans resulted in the constitutive activation of the MDR1 promoter and multidrug resistance. Therefore, mutations in MRR1 are the major cause of MDR1 upregulation in both C. albicans and C. dubliniensis, demonstrating that the transcription factor Mrr1p plays a central role in the development of drug resistance in these human fungal pathogens.
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