Sterol C-22 Desaturase ERG5 Mediates the Sensitivity to Antifungal Azoles in Neurospora crassa and Fusarium verticillioides

Sun, Xiepeng; Wang, Wenzhao; Wang, Kangji; Yu, Xinxu; Liu, Jie; Xie, Baogui; Li, Shaojie

doi:10.3389/fmicb.2013.00127

Cited by 31 publications

(39 citation statements)

References 41 publications

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“…To explain the reason for the increased sensitivity of Δerg4A Δerg4B to itraconazole and voriconazole, we first may exclude the mechanism mediated by ergosterol deficiency since a previous study in erg3 mutants with decreased ergosterol content has demonstrated that there was no significant difference in voriconazole susceptibility (17). Second, the possibility ofergosta-5,7,22,24(28)-tetraenol accumulation might also be excluded as the Δerg5 mutant with blocked production of ergosta-5,7,22,24(28)-tetraenol in Neurospora crassa or Fusarium verticillioides also exhibited increased susceptibility to azoles (32). Therefore, the reason for the increased susceptibility is probably the changed fluidity of membranes or the varied activities of membrane-located azole pumps, which may be affected in the absence of Erg4A and Erg4B.…”

Section: Discussionmentioning

confidence: 99%

Erg4A and Erg4B Are Required for Conidiation and Azole Resistance via Regulation of Ergosterol Biosynthesis in Aspergillus fumigatus

Long

Zeng

et al. 2017

Appl Environ Microbiol

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Ergosterol, a fungus-specific sterol enriched in cell plasma membranes, is an effective antifungal drug target. However, current knowledge of the ergosterol biosynthesis process in the saprophytic human fungal pathogen Aspergillus fumigatus remains limited. In this study, we found that two endoplasmic reticulumlocalized sterol C-24 reductases encoded by both erg4A and erg4B homologs are required to catalyze the reaction during the final step of ergosterol biosynthesis. Loss of one homolog of Erg4 induces the overexpression of the other one, accompanied by almost normal ergosterol synthesis and wild-type colony growth. However, double deletions of erg4A and erg4B completely block the last step of ergosterol synthesis, resulting in the accumulation of ergosta-5,7,22,24(28)-tetraenol, a precursor compound of ergosterol. Further studies indicate that erg4A and erg4B are required for conidiation but not for hyphal growth. Importantly, the Δerg4A Δerg4B mutant still demonstrates wild-type virulence in a compromised mouse model but displays remarkable increased susceptibility to antifungal azoles. Our data suggest that inhibitors of Erg4A and Erg4B may serve as effective candidates for adjunct antifungal agents with azoles.IMPORTANCE Knowledge of the ergosterol biosynthesis pathway in the human opportunistic pathogen A. fumigatus is useful for designing and finding new antifungal drugs. In this study, we demonstrated that the endoplasmic reticulum-localized sterol C-24 reductases Erg4A and Erg4B are required for conidiation via regulation of ergosterol biosynthesis. Moreover, inactivation of both Erg4A and Erg4B results in hypersensitivity to the clinical guideline-recommended antifungal drugs itraconazole and voriconazole. Therefore, our finding indicates that inhibition of Erg4A and Erg4B might be an effective approach for alleviating A. fumigatus infection.

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Section: Discussionmentioning

confidence: 99%

Erg4A and Erg4B Are Required for Conidiation and Azole Resistance via Regulation of Ergosterol Biosynthesis in Aspergillus fumigatus

Long

Zeng

et al. 2017

Appl Environ Microbiol

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“…ERG5 is a sterol C-22 desaturase that plays a role in ergosterol biosynthesis. Deletion of erg5 in N. crassa and Fusarium verticillioides caused hypersensitivity to azoles (25). The RNA-seq data showed that the erg5 transcript level in KTC-treated WT cells was 2.1-fold higher than that in non-KTC-treated WT cells.…”

Section: Ads-4 Responds Transcriptionally To Ketoconazole Inmentioning

confidence: 91%

“…CDR4 is the ortholog of the azole efflux pump Cdr1p in C. albicans (24). The roles of cdr4 and its orthologs in azole resistance in many fungi have been demonstrated previously (24,25,53). The ortholog of NcabcB in A. fumigates is the ABC multidrug transporter AbcB, which positively contributes to azole resistance (35,36).…”

Section: Discussionmentioning

confidence: 99%

“…This led to the discovery of a number of new azole-responsive genes that play important roles in azole resistance (20,24,25). One of the newly identified genes encodes a transcription factor in N. crassa that regulates the transcriptional responses to ketoconazole of 78 genes, including the azole-target-coding gene erg11 and the Pdr5p-like ABC-transporter-coding gene cdr4.…”

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confidence: 99%

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Transcription Factor ADS-4 Regulates Adaptive Responses and Resistance to Antifungal Azole Stress

Wang

Zhang

Chen

et al. 2015

Antimicrob Agents Chemother

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bAzoles are commonly used as antifungal drugs or pesticides to control fungal infections in medicine and agriculture. Fungi adapt to azole stress by rapidly activating the transcription of a number of genes, and transcriptional increases in some azole-responsive genes can elevate azole resistance. The regulatory mechanisms that control transcriptional responses to azole stress in filamentous fungi are not well understood. This study identified a bZIP transcription factor, ADS-4 (antifungal drug sensitive-4), as a new regulator of adaptive responses and resistance to antifungal azoles. Transcription of ads-4 in Neurospora crassa cells increased when they were subjected to ketoconazole treatment, whereas the deletion of ads-4 resulted in hypersensitivity to ketoconazole and fluconazole. In contrast, the overexpression of ads-4 increased resistance to fluconazole and ketoconazole in N. crassa. Transcriptome sequencing (RNA-seq) analysis, followed by quantitative reverse transcription (qRT)-PCR confirmation, showed that ADS-4 positively regulated the transcriptional responses of at least six genes to ketoconazole stress in N. crassa. The gene products of four ADS-4-regulated genes are known contributors to azole resistance, including the major efflux pump CDR4 (Pdr5p ortholog), an ABC multidrug transporter (NcAbcB), sterol C-22 desaturase (ERG5), and a lipid transporter (NcRTA2) that is involved in calcineurin-mediated azole resistance. Deletion of the ads-4-homologous gene Afads-4 in Aspergillus fumigatus caused hypersensitivity to itraconazole and ketoconazole, which suggested that ADS-4 is a functionally conserved regulator of adaptive responses to azoles. This study provides important information on a new azole resistance factor that could be targeted by a new range of antifungal pesticides and drugs. F ilamentous fungi cause over 70% of plant diseases, and some can cause deadly infections in humans (1-5). Azoles (e.g., itraconazole [ITA], fluconazole [FLC], and ketoconazole [KTC]) are the most commonly used antifungal drugs in medicine, and some azoles, such as triadimenol and propiconazole, are also used to control fungal diseases in plants (6). Antifungal azoles inhibit 14␣-methyl sterol demethylase (encoded by ERG11), a key enzyme involved in fungal ergosterol biosynthesis. This leads to changes in membrane consistency (7,8). In addition to blocking ergosterol production, the inhibition of ERG11 by azoles results in the accumulation of toxic 14␣-methylated sterol intermediates (9, 10).Fungi can adapt to azole stress by rapidly increasing the expression of a number of genes. Increased expression of some azoleresponsive genes, such as genes encoding azole efflux pumps and genes involved in ergosterol biosynthesis, can increase resistance to azoles (11,12). Previous studies in Saccharomyces cerevisiae and Candida albicans identified a number of regulatory genes that mediate azole responses. The transcription factors Pdr1p and Pdr3p in S. cerevisiae and their homologs in C. albicans regulate azole responses by c...

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“…Zaheer et al (2013) found that both therapeutic and subtherapeutic macrolide administration significantly increased the proportion of erythromycin resistant enterococci but had no effect on the development of macrolide resistance in Mannheimia haemolytica, both isolated from the nasopharynx. Sun et al (2013) reported that sterol C-22 desaturase ERG5, which is highly conserved among various fungal species, is involved in azole resistance and may serve as a novel target for antifungal drugs, in particular against Neurospora crassa and Fusarium verticillioides. Using the population-based multivariate analysis, Abbes et al (2013) observed that fluconazole resistance in Candida glabrata involves complex interactions between drug resistance gene expression and/or copy number.…”

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confidence: 99%

Mechanisms of antibiotic resistance

Cattoir

2015

Frontiers Research Topics

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Sterol C-22 Desaturase ERG5 Mediates the Sensitivity to Antifungal Azoles in Neurospora crassa and Fusarium verticillioides

Cited by 31 publications

References 41 publications

Erg4A and Erg4B Are Required for Conidiation and Azole Resistance via Regulation of Ergosterol Biosynthesis in Aspergillus fumigatus

Erg4A and Erg4B Are Required for Conidiation and Azole Resistance via Regulation of Ergosterol Biosynthesis in Aspergillus fumigatus

Transcription Factor ADS-4 Regulates Adaptive Responses and Resistance to Antifungal Azole Stress

Mechanisms of antibiotic resistance

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