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

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

Antimicrob Agents Chemother. 2020 Nov 16;:

Authors: Yin Y, Zhang H, Zhang Y, Hu C, Sun X, Liu W, Li S

Abstract
Antifungal azoles are the most widely used antifungal drugs in clinical and agricultural practice. Fungi can make adaptive responses to azole stress by modifying 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 transcript level of ads-1 was significantly increased in N. crassa Deletion of ads-1 increased the susceptibility to different azoles while its overexpression increased resistance to these azoles. The gene cdr4, 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 the cellular KTC accumulation under KTC stress while its overexpression had the opposite effect. ADS-1 also positively regulated 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 wild type, while ads-1 overexpression had the opposite effects. The homologs of ADS-1 widely present in filamentous fungal species of Ascomycota but not in yeasts. Deletion of the gene encoding ADS-1 homolog in Aspergillus flavus also increased the susceptibility to KTC and itraconazole (ITZ). Besides, deletion of Afads-1 significantly reduced the transcriptional response by genes encoding homologs of CDR4 and ERG11 in A. flavus to KTC stress and accumulated more KTC but less ergosterol. Together, 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.

PMID: 33199382 [PubMed – as supplied by publisher]

Source: Industry