Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1276313 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Aspergillus fumigatus transcription factor AtrR is a critical determinant of the azole resistance phenotype of this organism. AtrR positively regulates expression of a range of genes involved in azole resistance including the ATP-binding cassette transporter-encoding locus abcG1 (cdr1B/abcC) as well as the gene that encodes the enzymatic target of azole drugs cyp51A. Homology searches of A. fumigatus AtrR against a range of fungal species identified highly conserved 25 amino acid region in the carboxy-terminus. To determine the contribution of this region to AtrR function, we prepared a mutant from of the atrR that lacked this region (Δ855-879). We compared the response of an isogenic wild-type strain to a strain expressing the Δ855-879 AtrR derivative using RNA-seq, both in the absence and the presence of voriconazole challenge. The resulting data indicate that this 25 amino acid segment of AtrR is required for expression of some but not all AtrR target genes.
2024-08-08 | GSE267651 | GEO
Project description:The Negative cofactor 2 (NCT) complex is an evolutionally conserved heterodimeric transcription factor. In Aspergillus fumigatus, the NCT complex consists of two subunits NctA and NctB. Through a genome-wide screening of a transcription factor null mutant strains, we found that loss of the NCT complex leads to a multi-drug resistance phenotype including the azoles (itraconazole, voriconazole and posaconazole) as well as the salvage therapeutic amphotericin B, and terbinafine. To obtain further insight into the molecular mechanisms driving the azole-resistance in the NCT complex null mutants, we analyzed genome-wide binding profiles of NctA using chromatin-immunoprecipitation sequencing (ChIP-seq). Our ChIP-seq analysis revealed that NCT complex binds the promoters of several ergosterol biosynthetic genes, their transcriptional regulators, and the azole efflux pump cdr1B. Taken together, these results suggest that the NCT complex plays a role as a master regulator of drug resistance in A. fumigatus.
2019-12-31 | GSE129967 | GEO
Project description:As a major fungal pathogen, Aspergillus fumigatus can induce chronic, allergic or severe invasive infections, meanwhile its escalating resistance to azole antifungals has emerged as a global public health menace. Squalene, an essential molecule in the sterol biosynthesis pathway, can be cyclized by squalene hopene cyclase (SHC) to produce hopanoids and affect probably sterol biosynthesis modifying azole resistance; however, the physiological function of SHC in A. fumigatus pathogenesis is poorly understood.
2026-02-03 | GSE317610 | GEO
Project description:The Negative cofactor 2 (NCT) complex is an evolutionally conserved heterodimeric transcription factor. In Aspergillus fumigatus, the NCT complex consists of two subunits NctA and NctB. Through a genome-wide screening of a transcription factor null mutant strains, we found that loss of the NCT complex leads to a multi-drug resistance phenotype including the azoles (itraconazole, voriconazole and posaconazole) as well as the salvage therapeutic amphotericin B, and terbinafine. To obtain further insight into the molecular mechanisms driving the azole-resistance in the NCT complex null mutants, we analyzed genome-wide gene expression profiles of the nctA and the nctB null mutants using RNA-seq. Our expression profiling revealed that disruption of the genes lead to upregulation of several ergosterol biosynthetic genes, their transcriptional activators, and the azole efflux pump cdr1B. Taken together, these results suggest that the NCT complex plays a role as a master regulator of drug resistance in A. fumigatus.
2019-12-31 | GSE133464 | GEO
Project description:Genome sequence data results are reported from experimental and bioinfomatic work using the technique 'Bulk Segregant Analysis' to determine the genetic basis of observed resistance to the azole antifungal compound itraconazole in the opportunistic fungal pathogen Aspergillus fumigatus.
2022-05-11 | GSE193956 | GEO
Project description:The widespread use of azole antifungal drugs in agriculture and clinical settings has led to serious drug resistance issues. Under azole treatment, resistant strains can upregulate the expression of the azole drug target 14α-demethylase ERG11 through transcription factors to alleviate the stress induced by sterol synthesis inhibition, which is a common resistance mechanism. Additionally, the currently reported regulatory factors related to resistance are not sufficient to explain all resistance issues. In this study, we constructed a GFP gene reporter system based on the erg11 promoter in the model filamentous fungus, Neurospora crassa, and identified a key region of the promoter that governs the erg11 response to azole drug by stepwise deletion. Using specific probes for DNA pulldown and combined with phenotype analysis, we identified a protein, Crf4-3, containing a PWWP domain that has a positive regulatory effect. Specific deletion of Crf4-3 leads to hypersensitivity to azole drugs and loss of transcriptional response of erg11 and erg6 to ketoconazole. Furthermore, the basal expression of erg1, erg11, erg25, and erg3A is affected by the deletion of crf4-3. Crf4-3 homologs are widely present in the Pezizomycotina fungi. Deletion of the homologous protein of Crf4-3 in Aspergillus fumigatus also significantly reduced sensitivity to azole drugs like voriconazole by reducing the transcriptional response of erg11. In summary, our study revealed a new regulatory factor Crf4-3 involved in the azole stress response in filamentous fungi and its mechanism, providing new insights into understanding the mechanisms of azole drug resistance.
2024-09-15 | GSE272185 | GEO
Project description:Azole antifungals are widely used to control fungal infection, yet resistance mechanisms beyond drug efflux and target modification remain insufficiently understood. Here, we identified the Guided Entry of Tail-anchored proteins (GET) pathway as a conserved regulator of azole susceptibility in Neurospora crassa and Aspergillus fumigatus. Deletion or dysfunction of the core GET components Get-3 or Get-4 confers resistance to multiple azoles without impairing hyphal growth or sporulation. Mechanistically, GET deficiency neither reduced intracellular accumulation nor altered drug efflux and target expression or total ergosterol levels. Instead, GET-deficient strains displayed significantly reduced accumulation of the toxic sterol intermediate 14α-methyl-3,6-diol under azole stress, indicating a potential bypass of azole-induced sterol toxicity. Proximity labeling and functional validation indicated that GET deficiency perturbs the trafficking of multiple azole-resistance-associated proteins, including the key tail-anchored protein transporter Emp-47 and mitochondrial Cox subunits Cox-4 and Cox-15, which deletion enhanced azole resistance. Transcriptomic and functional analysis further revealed that GET disruption altered the expression of some azole resistance-associated genes, which involve in membrane transport, metabolism, and cell wall organization, independent of canonical stress pathways. In this study, a total of 17 new genes that modulate azole susceptibility were identified. Collectively, our findings uncover a non-classical mechanism of azole resistance mediated by GET-dependent protein trafficking and metabolic adaptation, conserved across filamentous fungi.
2026-04-01 | PXD076447 |