Elevated mutation rates in multi-azole resistant Aspergillus fumigatus drive rapid evolution of antifungal resistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB81974 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR13925066_1.fastq.gz | Fastqsanger.gz | |||
| ERR13925066_2.fastq.gz | Fastqsanger.gz | |||
| ERR13925067_1.fastq.gz | Fastqsanger.gz | |||
| ERR13925067_2.fastq.gz | Fastqsanger.gz | |||
| ERR13925068_1.fastq.gz | Fastqsanger.gz |
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2014-05-24 | GSE57929 | GEO
Project description:In Candida albicans, the transcription factor Upc2 is central to the regulation of ergosterol biosynthesis. UPC2-activating mutations contribute to azole resistance, whereas disruption increases azole susceptibility. In the present study, we investigated the relationship of UPC2 to fluconazole susceptibility, particularly in azole-resistant strains. In addition to the reduced fluconazole MIC previously observed with UPC2 disruption, we observed a lower minimum fungicidal concentration (MFC) for a upc2M-NM-^T/M-NM-^T mutant than for its azole-susceptible parent, SC5314. Moreover, the upc2M-NM-^T/M-NM-^T mutant was unable to grow on a solid medium containing 10 M-BM-5g/ml fluconazole and exhibited increased susceptibility and a clear zone of inhibition by Etest. Time-kill analysis showed higher fungistatic activity against the upc2M-NM-^T/M-NM-^T mutant than against SC5314. UPC2 disruption in strains carrying specific resistance mutations also resulted in reduced MICs and MFCs. UPC2 disruption in a highly azole resistant clinical isolate containing multiple resistance mechanisms likewise resulted in a reduced MIC and MFC. This mutant was unable to grow on a solid medium containing 10 M-BM-5g/ml fluconazole and exhibited increased susceptibility and a clear zone of inhibition by Etest. Time-kill analysis showed increased fungistatic activity against the upc2M-NM-^T/M-NM-^T mutant in the resistant background. Microarray analysis showed attenuated induction by fluconazole of genes involved in sterol biosynthesis, iron transport, or iron homeostasis in the absence of UPC2. Taken together, these data demonstrate that the UPC2 transcriptional network is universally essential for azole resistance in C. albicans and represents an attractive target for enhancing azole antifungal activity. We examined the genome-wide gene expression profiles of the wild-type parent strain SC5314 and its upc2M-NM-^T/M-NM-^T derivative in response to fluconazole in order to identify genes whose expression in response to fluconazole is influenced by Upc2.
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Project description:The mechanism of action of the new antifungal compound 089 was identified in Saccharomyces cerevisiae. The compound had antifungal effects also on pathogenic fungi. While on Candida species the treatment induced cells death, on A. fumigatus strains it inhibited the conidia transition to hyphae. We carried out RNA sequencing analysis to evaluate at the molecular level the effect of the treatment on Aspergillus.
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