Phenotypic heterogeneity guides adaptive evolution
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR895070_1.fastq.gz | Fastqsanger.gz | |||
| ERR895070_2.fastq.gz | Fastqsanger.gz | |||
| ERR895071_1.fastq.gz | Fastqsanger.gz | |||
| ERR895071_2.fastq.gz | Fastqsanger.gz | |||
| ERR895072_1.fastq.gz | Fastqsanger.gz |
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Project description:The leucine CUG codon was reassigned to serine in the fungal pathogen Candida albicans. To clarify the biological role of this tuneable codon ambiguity on drug resistance, we evolved C. albicans strains that were engineered to mistranslate the CUG codon at constitutively elevated levels, in the presence and absence of the antifungal drug fluconazole. Elevated levels of mistranslation resulted in the rapid acquisition of resistance to fluconazole.
2016-10-27 | E-SYBR-13 | biostudies-arrayexpress
Project description:The fungal pathogen Candida albicans and other pathogens of the CTG clade reassigned the leucine CUG codon to serine and tolerate highly variable levels of both serine and leucine at CUG positions in response to environmental cues. Previous studies found that increased leucine misincorporation levels enhance resistance to drugs but the underlying mechanisms are not known. To clarify the biological role of this tuneable codon ambiguity, we evolved C. albicans strains engineered to mistranslate CUG at elevated levels, in the presence and absence of the antifungal drug fluconazole
2017-07-18 | GSE60121 | GEO
Project description:The fungal pathogen Candida albicans and other pathogens of the CTG clade reassigned the leucine CUG codon to serine and tolerate highly variable levels of both serine and leucine at CUG positions in response to environmental cues. Previous studies found that increased leucine misincorporation levels enhance resistance to drugs but the underlying mechanisms are not known. To clarify the biological role of this tuneable codon ambiguity, we evolved C. albicans strains engineered to mistranslate CUG at elevated levels, in the presence and absence of the antifungal drug fluconazole
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Project description:Genome-wide assays to test the interaction between two independently evolved mechanisms of fluconazole resistance Keywords: Comparative genomic hybridization
2006-07-15 | GSE4261 | GEO
Project description:We examined the gene expression changes resulting from the evolution of resistance in experimental populations of the yeast Saccharomyces cerevisiae subjected to two antifungal drugs, fluconazole (FLC) and amphotericin B (AmB). Fluconazole resistance may involve increased efflux or changes in sterol metabolism, while AmB resistance generally involves changes in sterol metabolism; for all of these types of resistance, the gene expression changes are extensive. The goal of these experiments was to test whether failure of gene expression changes all downstream of the original mutation for drug resistance would affect the ability of a mutant cell to evolve and/or to support a drug-resistant phenotype.
2008-07-28 | GSE12055 | GEO
Project description:The identification of novel transcription factors associated to antifungal response may allow the discovery of fungal specific targets for new therapeutic strategies. A collection of 241 C. albicans transcriptional regulators mutants was screened for altered susceptibility to fluconazole, caspofungin, amphotericin B, and 5-fluorocytosine. Thirteen of these mutants not yet identified in their role in antifungal response were further investigated, and the function of one of them, mutant for orf19.6102 (RCA1) was characterized by transcriptome analysis. Strand specific RNA sequencing and phenotypic tests assigned Rca1 as the regulator of hyphal formation through the cAMP/PKA signaling pathway and the transcription factor Efg1, but also probably through its interaction with a transcriptional repressor, most likely Tup1. The mechanisms responsible for the high level of resistance to caspofungin and fluconazole observed resulting from Rca1 deletion were investigated. From our observations, we propose that caspofungin resistance was the consequence of the deregulation of cell wall gene expression, and that fluconazole resistance was linked to the modulation of the cAMP/PKA signaling pathway activity. In conclusion, our large-scale screening of a C. albicans transcription factor mutants collection allowed the identification of new effectors of the response to antifungals. The functional characterization of Rca1 assigned this TF and its downstream targets as promising candidates for the development of new therapeutic strategies, as Rca1 influences host sensing, hyphal development, and antifungal response.
2012-05-02 | GSE37682 | GEO
Project description:The identification of novel transcription factors associated to antifungal response may allow the discovery of fungal specific targets for new therapeutic strategies. A collection of 241 C. albicans transcriptional regulators mutants was screened for altered susceptibility to fluconazole, caspofungin, amphotericin B, and 5-fluorocytosine. Thirteen of these mutants not yet identified in their role in antifungal response were further investigated, and the function of one of them, mutant for orf19.6102 (RCA1) was characterized by transcriptome analysis. Strand specific RNA sequencing and phenotypic tests assigned Rca1 as the regulator of hyphal formation through the cAMP/PKA signaling pathway and the transcription factor Efg1, but also probably through its interaction with a transcriptional repressor, most likely Tup1. The mechanisms responsible for the high level of resistance to caspofungin and fluconazole observed resulting from Rca1 deletion were investigated. From our observations, we propose that caspofungin resistance was the consequence of the deregulation of cell wall gene expression, and that fluconazole resistance was linked to the modulation of the cAMP/PKA signaling pathway activity. In conclusion, our large-scale screening of a C. albicans transcription factor mutants collection allowed the identification of new effectors of the response to antifungals. The functional characterization of Rca1 assigned this TF and its downstream targets as promising candidates for the development of new therapeutic strategies, as Rca1 influences host sensing, hyphal development, and antifungal response. Total RNAs from RCA1 mutant and revertant isolates were extracted in duplicate from exponential growth-phase cultures in YEPD media. Differential expression was resolved by strand specific RNA sequencing.
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Project description:Aneuploidy and the evolution of aneuploid karyotypes of Candida albicans strains was identified using aCGH. Whole chromosome and segmental aneuploidies, (specifically on the left arm of chromosome 5 - shown to be due to isochromosome formation) are associated with the appearance of resistance to the antifungal drug fluconazole. Keywords: Comparative Genomic Hybridization
2006-06-30 | GSE4995 | GEO
Project description:Azole antifungal agents such as fluconazole exhibit fungistatic activity against Candida albicans. Strategies to enhance azole antifungal activity would be therapeutically appealing. In an effort to identify transcriptional pathways that influence fluconazole susceptibility, we sought to identify transcription factors (TFs) involved in this process. From a collection of C. albicans strains disrupted for genes encoding TFs (Homann et al., PLoS Genet. 2009;5:e1000783), four exhibited a marked reduction in minimum fungicidal concentration (MFC) in both RPMI and YPD media. One of these, UPC2, has been previously characterized with regard to its role in azole susceptibility. Of mutants representing the three remaining TF genes of interest, one (CAS5) was unable to recover from fluconazole exposure at concentrations as low as 2 M-BM-5g/mL after 72 hours in YPD medium. This mutant also showed reduced susceptibility and a clear zone of inhibition by Etest, was unable to grow on solid media containing 10 M-BM-5g/mL fluconazole, and exhibited increased susceptibility by time-kill analysis. CAS5 disruption in highly azole-resistant clinical isolates exhibiting multiple resistance mechanisms did not alter susceptibility. However, CAS5 disruption in strains with specific resistance mutations in ergosterol biosynthesis or efflux pumps resulted in a moderate reduction in MIC and MFC. Genome-wide transcriptional analysis was performed in the presence of fluconazole and was consistent with the suggested role of CAS5 in cell wall organization while also suggesting a role in iron transport and homeostasis. These findings suggest that Cas5 regulates a transcriptional network that influences susceptibility of C. albicans to fluconazole. Further delineation of this transcriptional network may identify targets for potential co-therapeutic strategies to enhance the activity to the azole class of antifungals. We examined the genome-wide gene expression profiles of the wild-type parent strain SC5314 and its cas5M-NM-^T/M-NM-^T derivative in response to fluconazole in order to identify genes whose expression in response to fluconazole is influenced by Cas5.
2014-05-24 | E-GEOD-57930 | biostudies-arrayexpress
Project description:Azole antifungal agents such as fluconazole exhibit fungistatic activity against Candida albicans. Strategies to enhance azole antifungal activity would be therapeutically appealing. In an effort to identify transcriptional pathways that influence fluconazole susceptibility, we sought to identify transcription factors (TFs) involved in this process. From a collection of C. albicans strains disrupted for genes encoding TFs (Homann et al., PLoS Genet. 2009;5:e1000783), four exhibited a marked reduction in minimum fungicidal concentration (MFC) in both RPMI and YPD media. One of these, UPC2, has been previously characterized with regard to its role in azole susceptibility. Of mutants representing the three remaining TF genes of interest, one (CAS5) was unable to recover from fluconazole exposure at concentrations as low as 2 µg/mL after 72 hours in YPD medium. This mutant also showed reduced susceptibility and a clear zone of inhibition by Etest, was unable to grow on solid media containing 10 µg/mL fluconazole, and exhibited increased susceptibility by time-kill analysis. CAS5 disruption in highly azole-resistant clinical isolates exhibiting multiple resistance mechanisms did not alter susceptibility. However, CAS5 disruption in strains with specific resistance mutations in ergosterol biosynthesis or efflux pumps resulted in a moderate reduction in MIC and MFC. Genome-wide transcriptional analysis was performed in the presence of fluconazole and was consistent with the suggested role of CAS5 in cell wall organization while also suggesting a role in iron transport and homeostasis. These findings suggest that Cas5 regulates a transcriptional network that influences susceptibility of C. albicans to fluconazole. Further delineation of this transcriptional network may identify targets for potential co-therapeutic strategies to enhance the activity to the azole class of antifungals.
2014-05-24 | GSE57930 | GEO