Mutations in transcription factor Mrr2p contribute to fluconazole resistance in clinical isolates of Candida albicans

Wang, Ying; Liu, Jinyan; Shi, Ce; Li, Wenjing; Zhao, Yuwu; Yan, Lan; Xiang, Ming-Jie

doi:10.1016/j.ijantimicag.2015.08.001

Cited by 16 publications

(20 citation statements)

References 27 publications

(43 reference statements)

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“…Clinically derived MRR2 alleles were introduced in a fluconazolesusceptible background to generate strains containing multiple single nucleotide polymorphisms (SNPs) in the MRR2 gene. In contrast to a previous report (28), we found no changes in fluconazole MIC or CDR1 expression upon introduction of any of the MRR2 SNPs observed in clinical isolates in our collection or that had been described previously.…”

contrasting

confidence: 99%

“…Three of these substitutions (R45Q, A459T, V486M) had not previously been described in the literature. The remaining four substitutions (S466L, A468G, S469T, T470N) had been previously found in resistant clinical C. albicans isolates and were reported to have an effect on fluconazole MIC and CDR1 expression (28). Within our collection, these four substitutions appeared in four clinical isolates and exclusively co-occurred with each other.…”

Section: Resultsmentioning

confidence: 51%

“…Additionally, fluconazole sensitivity was restored after deletion of the CDR1 gene in the hyperactive Mrr2 strain (14). More recently, potential activating mutations in Mrr2 which increased expression of CDR1 but not CDR2 have been described in fluconazole-resistant clinical isolates of C. albicans, indicating not only that these mechanisms can manifest in vitro but also that they are clinically relevant (28). Mrr2 is a relatively understudied ZCF whose role in clinical azole resistance has not yet been completely defined, but the potential significance of Mrr2 as a contributing azole resistance determinant in C. albicans cannot be overlooked.…”

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confidence: 96%

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Contribution of Clinically Derived Mutations in the Gene Encoding the Zinc Cluster Transcription Factor Mrr2 to Fluconazole Antifungal Resistance and CDR1 Expression in Candida albicans

Nishimoto

Zhang

Hazlett

et al. 2019

Antimicrob Agents Chemother

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Mutations in genes encoding zinc cluster transcription factors (ZCFs) such as TAC1, MRR1, and UPC2 play a key role in Candida albicans azole antifungal resistance. Artificial activation of the ZCF Mrr2 has shown increased expression of the gene encoding the Cdr1 efflux pump and resistance to fluconazole. Amino acid substitutions in Mrr2 have recently been reported to contribute to fluconazole resistance in clinical isolates. In the present study, 57 C. albicans clinical isolates with elevated fluconazole MICs were examined for mutations in MRR2 and expression of CDR1. Mutations in MRR2 resulting in 15 amino acid substitutions were uniquely identified among resistant isolates, including 4 substitutions (S466L, A468G, S469T, T470N) previously reported to reduce fluconazole susceptibility. Three additional, novel amino acid substitutions (R45Q, A459T, V486M) were also discovered in fluconazole-resistant isolates. When introduced into a fluconazole-susceptible background, no change in fluconazole MIC or CDR1 expression was observed for any of the mutations found in this collection. However, introduction of an allele leading to artificial activation of Mrr2 increased resistance to fluconazole as well as CDR1 expression. Moreover, Mrr2 amino acid changes reported previously to have the strongest effect on fluconazole susceptibility and CDR1 expression also exhibited no differences in fluconazole susceptibility or CDR1 expression relative to the parent strain. While all known fluconazole resistance mechanisms are represented within this collection of clinical isolates and contribute to fluconazole resistance to different extents, mutations in MRR2 do not appear to alter CDR1 expression or contribute to resistance in any of these isolates.

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confidence: 99%

Section: Resultsmentioning

confidence: 51%

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confidence: 96%

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Contribution of Clinically Derived Mutations in the Gene Encoding the Zinc Cluster Transcription Factor Mrr2 to Fluconazole Antifungal Resistance and CDR1 Expression in Candida albicans

Nishimoto

Zhang

Hazlett

et al. 2019

Antimicrob Agents Chemother

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“…albicans isolates. Indeed, three epidemiologically related isolates with elevated CDR1 expression levels contained a mutated MRR2 allele that caused CDR1 overexpression and increased fluconazole resistance when introduced into a drug-susceptible strain, demonstrating the clinical relevance of the predicted resistance mechanism [35]. …”

Section: Introductionmentioning

confidence: 99%

An acquired mechanism of antifungal drug resistance simultaneously enables Candida albicans to escape from intrinsic host defenses

et al. 2017

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The opportunistic fungal pathogen Candida albicans frequently produces genetically altered variants to adapt to environmental changes and new host niches in the course of its life-long association with the human host. Gain-of-function mutations in zinc cluster transcription factors, which result in the constitutive upregulation of their target genes, are a common cause of acquired resistance to the widely used antifungal drug fluconazole, especially during long-term therapy of oropharyngeal candidiasis. In this study, we investigated if C. albicans also can develop resistance to the antimicrobial peptide histatin 5, which is secreted in the saliva of humans to protect the oral mucosa from pathogenic microbes. As histatin 5 has been shown to be transported out of C. albicans cells by the Flu1 efflux pump, we screened a library of C. albicans strains that contain artificially activated forms of all zinc cluster transcription factors of this fungus for increased FLU1 expression. We found that a hyperactive Mrr1, which confers fluconazole resistance by upregulating the multidrug efflux pump MDR1 and other genes, also causes FLU1 overexpression. Similarly to the artificially activated Mrr1, naturally occurring gain-of-function mutations in this transcription factor also caused FLU1 upregulation and increased histatin 5 resistance. Surprisingly, however, Mrr1-mediated histatin 5 resistance was mainly caused by the upregulation of MDR1 instead of FLU1, revealing a previously unrecognized function of the Mdr1 efflux pump. Fluconazole-resistant clinical C. albicans isolates with different Mrr1 gain-of-function mutations were less efficiently killed by histatin 5, and this phenotype was reverted when MRR1 was deleted. Therefore, antimycotic therapy can promote the evolution of strains that, as a consequence of drug resistance mutations, simultaneously have acquired increased resistance against an innate host defense mechanism and are thereby better adapted to certain host niches.

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“…Tac1-indepndent CDR1 induction by farnesol can be largely attributed to Znc1 (and Mrr2) function. Interestingly, unlike Tac1 (27) and Mrr2 (52), no gain-of-function mutants of Znc1 have been reported to drive azole resistance in C. albicans . Of the well-characterized CDR1 inducers, farnesol is the only one considered to be a C. albicans metabolite.…”

Section: Discussionmentioning

confidence: 99%

C. albicans Zn Cluster Transcription Factors Tac1 and Znc1 are Activated by Farnesol to Up Regulate a Transcriptional Program Including the Multi-Drug Efflux Pump CDR1

Liu

Rossi

Myers

2018

Preprint

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15Farnesol, a quorum-sensing molecule, inhibits C. albicans hyphal formation, affects 16 its biofilm formation and dispersal, and impacts its stress response. Several aspects 17 of farnesol's mechanism of action remain incompletely uncharacterized. Among 18 these are a thorough accounting of the cellular receptors and transporters for farnesol. 19This work suggests these themes are linked through the Zn cluster transcription 20 factors Tac1 and Znc1, and their induction of the multi-drug efflux pump Cdr1.

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Mutations in transcription factor Mrr2p contribute to fluconazole resistance in clinical isolates of Candida albicans

Cited by 16 publications

References 27 publications

Contribution of Clinically Derived Mutations in the Gene Encoding the Zinc Cluster Transcription Factor Mrr2 to Fluconazole Antifungal Resistance and CDR1 Expression in Candida albicans

Contribution of Clinically Derived Mutations in the Gene Encoding the Zinc Cluster Transcription Factor Mrr2 to Fluconazole Antifungal Resistance and CDR1 Expression in Candida albicans

An acquired mechanism of antifungal drug resistance simultaneously enables Candida albicans to escape from intrinsic host defenses

C. albicans Zn Cluster Transcription Factors Tac1 and Znc1 are Activated by Farnesol to Up Regulate a Transcriptional Program Including the Multi-Drug Efflux Pump CDR1

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