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Mechanisms of Resistance

Fungal Zn(II)2Cys6 Transcription Factor ADS-1 Regulates Drug Efflux and Ergosterol Metabolism under Antifungal Azole Stress

Yajing Yin, Hanxing Zhang, Yu Zhang, Chengcheng Hu, Xianyun Sun, Wei Liu, Shaojie Li
Yajing Yin
aState Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
bUniversity of Chinese Academy of Sciences, Beijing, China
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Hanxing Zhang
aState Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
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Yu Zhang
aState Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
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Chengcheng Hu
aState Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
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Xianyun Sun
aState Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
bUniversity of Chinese Academy of Sciences, Beijing, China
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Wei Liu
cDepartment of Dermatology, Peking University First Hospital, Beijing, China
dResearch Center for Medical Mycology, Peking University, Beijing, China
eNational Clinical Research Center for Skin and Immune Diseases, Beijing, China
fBeijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China
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Shaojie Li
aState Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
bUniversity of Chinese Academy of Sciences, Beijing, China
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  • ORCID record for Shaojie Li
DOI: 10.1128/AAC.01316-20
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ABSTRACT

Antifungal azoles are the most widely used antifungal drugs in clinical and agricultural practice. Fungi can mount adaptive responses to azole stress by modifying the transcript levels of many genes, and the responsive mechanisms to azoles are the basis for fungi to develop azole resistance. In this study, we identified a new Zn(II)2Cys6 transcription factor, ADS-1, with a positive regulatory function in transcriptional responses to azole stress in the model filamentous fungal species Neurospora crassa. Under ketoconazole (KTC) stress, the ads-1 transcript level was significantly increased in N. crassa. Deletion of ads-1 increased susceptibility to different azoles, while its overexpression increased resistance to these azoles. The cdr4 gene, which encodes the key azole efflux pump, was positively regulated by ADS-1. Deletion of ads-1 reduced the transcriptional response by cdr4 to KTC stress and increased cellular KTC accumulation under KTC stress, while ads-1 overexpression had the opposite effect. ADS-1 also positively regulated the transcriptional response by erg11, which encodes the azole target lanosterol 14α-demethylase for ergosterol biosynthesis, to KTC stress. After KTC treatment, the ads-1 deletion mutant had less ergosterol but accumulated more lanosterol than the wild type, while ads-1 overexpression had the opposite effect. Homologs of ADS-1 are widely present in filamentous fungal species of Ascomycota but not in yeasts. Deletion of the gene encoding an ADS-1 homolog in Aspergillus flavus also increased susceptibility to KTC and itraconazole (ITZ). Besides, deletion of A. flavus ads-1 (Afads-1) significantly reduced the transcriptional responses by genes encoding homologs of CDR4 and ERG11 in A. flavus to KTC stress, and the deletion mutant accumulated more KTC but less ergosterol. Taken together, these findings demonstrate that the function and regulatory mechanism of ADS-1 homologs among different fungal species in azole responses and the basal resistance of azoles are highly conserved.

FOOTNOTES

    • Received 24 June 2020.
    • Returned for modification 21 August 2020.
    • Accepted 7 October 2020.
    • Accepted manuscript posted online 16 November 2020.
  • Supplemental material is available online only.

  • Copyright © 2021 American Society for Microbiology.

All Rights Reserved.

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Fungal Zn(II)2Cys6 Transcription Factor ADS-1 Regulates Drug Efflux and Ergosterol Metabolism under Antifungal Azole Stress
Yajing Yin, Hanxing Zhang, Yu Zhang, Chengcheng Hu, Xianyun Sun, Wei Liu, Shaojie Li
Antimicrobial Agents and Chemotherapy Jan 2021, 65 (2) e01316-20; DOI: 10.1128/AAC.01316-20

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Fungal Zn(II)2Cys6 Transcription Factor ADS-1 Regulates Drug Efflux and Ergosterol Metabolism under Antifungal Azole Stress
Yajing Yin, Hanxing Zhang, Yu Zhang, Chengcheng Hu, Xianyun Sun, Wei Liu, Shaojie Li
Antimicrobial Agents and Chemotherapy Jan 2021, 65 (2) e01316-20; DOI: 10.1128/AAC.01316-20
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KEYWORDS

azole
transcription factor
drug resistance
Neurospora crassa
Aspergillus flavus
antifungal drug

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