Fungal Zn(II) 2 Cys 6 Transcription Factor ADS-1 Regulates Drug Efflux and Ergosterol Metabolism under Antifungal Azole Stress.

Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 0315061 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1098-6596 (Electronic) Linking ISSN: 00664804 NLM ISO Abbreviation: Antimicrob Agents Chemother Subsets: MEDLINE

Original Publication: Washington, American Society for Microbiology

Azoles*/pharmacology ; Pharmaceutical Preparations*; Antifungal Agents/pharmacology ; Drug Resistance, Fungal/genetics ; Ergosterol ; Transcription Factors/genetics ; Zinc

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) 2 Cys 6 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 (Af ads-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.
(Copyright © 2021 American Society for Microbiology.)

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Keywords: Aspergillus flavus; Neurospora crassa; antifungal drug; azole; drug resistance; transcription factor

0 (Antifungal Agents)
0 (Azoles)
0 (Pharmaceutical Preparations)
0 (Transcription Factors)
J41CSQ7QDS (Zinc)
Z30RAY509F (Ergosterol)

Date Created: 20201117 Date Completed: 20210617 Latest Revision: 20210721

20240829

PMC7848988

10.1128/AAC.01316-20

33199382