Copper acts synergistically with fluconazole in Candida glabrata by compromising drug efflux, zinc homeostasis and sterol metabolism
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA682828 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13204887.fastq.gz | Fastqsanger.gz | |||
| SRR13204888.fastq.gz | Fastqsanger.gz | |||
| SRR13204889.fastq.gz | Fastqsanger.gz | |||
| SRR13204890.fastq.gz | Fastqsanger.gz | |||
| SRR13204891.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:In this study we used a transcriptomic approach to study the molecular determinants of the synergy between copper and fluconazole, in Candida glabrata, the second most frequent cause of invasive candidiasis. We demonstrate that copper acts together with fluconazole by downregulating three distinct pathways: azole efflux, ergosterol biosynthesis and zinc homeostasis. Coincidently, all these pathways are important for C. glabrata to cope with fluconazole stress. Therefore, when copper and fluconazole are combined cells fail to detoxify this drug and accumulate toxic methylated intermediates of sterol metabolism. This accumulation, possibly together with copper-induced lipid damages, should affect the activity of plasma membrane transporters, which impedes zinc uptake, leading to zinc depletion
2022-06-01 | GSE162741 | GEO
Project description:The synergistic combinations of drugs are promising strategies to boost the effectiveness of current antifungals and thus prevent the emergence of resistance. In this work, we show that copper and the antifungal fluconazole act synergistically against Candida glabrata, an opportunistic pathogenic yeast intrinsically tolerant to fluconazole. Analyses of the transcriptomic profile of C. glabrata after the combination of copper and fluconazole showed that the expression of the multidrug transporter gene CDR1 was decreased, suggesting that fluconazole efflux could be affected. In agreement, we observed that copper inhibits the transactivation of Pdr1, the transcription regulator of multidrug transporters and leads to the intracellular accumulation of fluconazole. Copper also decreases the transcriptional induction of ergosterol biosynthesis (ERG) genes by fluconazole, which culminates in the accumulation of toxic sterols. Co-treatment of cells with copper and fluconazole should affect the function of proteins located in the plasma membrane, as several ultrastructural alterations, including irregular cell wall and plasma membrane and loss of cell wall integrity, were observed. Finally, we show that the combination of copper and fluconazole downregulates the expression of the gene encoding the zinc-responsive transcription regulator Zap1, which possibly, together with the membrane transporters malfunction, generates zinc depletion. Supplementation with zinc reverts the toxic effect of combining copper with fluconazole, underscoring the importance of this metal in the observed synergistic effect. Overall, this work, while unveiling the molecular basis that supports the use of copper to enhance the effectiveness of fluconazole, paves the way for the development of new metal-based antifungal strategies.
| S-EPMC9237516 | biostudies-literature
Project description:<p><em>Trichosporon asahii</em> is a basidiomycete yeast that is pathogenic to humans and animals, and fluconazole-resistant strains have recently increased. Farnesol secreted by fungi is a factor that causes variations in fluconazole resistance; however, few studies have explored the underlying mechanisms. Therefore, this study aims to delineate the fluconazole resistance mechanisms of <em>T. asahii</em> and explore farnesol’s effects on these processes. A comparative metabolome-transcriptome analysis of untreated fluconazole-sensitive (YAN), fluconazole-resistant (PB) <em>T. asahii</em> strains and 25 μM farnesol-treated strains (YAN-25 and PB-25, respectively) was performed. The membrane lipid-related genes and metabolites were upregulated in the PB vs YAN and PB-25 vs PB comparisons. Farnesol demonstrated strain-dependent mechanisms underlying fluconazole tolerance between the YAN and PB strains, and upregulated and downregulated efflux pumps in PB-25 and YAN-25 strains, respectively. Membrane lipid-related metabolites were highly correlated with transporter-coding genes. Fluconazole resistance in <em>T. asahii</em> was induced by membrane lipid bio-synthesis activation. Farnesol inhibited fluconazole resistance in the sensitive strain, but enhanced resistance in the resistant strain by upregulating efflux pump genes and membrane lipids. This study offers valuable insights into the mechanisms underlying fungal drug resistance and provides guidance for future research aimed at developing more potent antifungal drugs for clinical use.</p><p><br></p>
2023-11-20 | MTBLS7236 | MetaboLights
Project description:Fungal infections are an emerging health risk, especially those involving yeast that are resistant to antifungal agents. To understand the range of mechanisms by which yeasts can respond to anti-fungals, we compared gene expression patterns across three evolutionarily distant species - Saccharomyces cerevisiae, Candida glabrata and Kluyveromyces lactis - over time following fluconazole exposure. Conserved and diverged expression patterns were identified using a novel soft clustering algorithm that concurrently clusters data from all species while incorporating sequence orthology. The analysis suggests complementary strategies for coping with ergosterol depletion by azoles - Saccharomyces imports exogenous ergosterol, Candida exports fluconazole, while Kluyveromyces does neither leading to extreme sensitivity. In support of this hypothesis we find that only Saccharomyces becomes more azole resistant in ergosterol-supplemented media; that this depends on sterol importers Aus1 and Pdr11; and that transgenic expression of sterol importers in Kluyveromyces alleviates its drug sensitivity. We have compared the dynamic transcriptional responses of three diverse yeast species to fluconazole treatment using a novel clustering algorithm. This approach revealed significant divergence among regulatory programs associated with fluconazole sensitivity. In future, such approaches might be used to survey a wider range of species, drug concentrations and stimuli to reveal conserved and divergent molecular response pathways.
2010-07-08 | GSE15710 | 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 goal of this RNA-Seq study is to elucidate Rpn4’s function in regulating C. auris fluconazole resistance.
2023-11-15 | GSE218140 | GEO
Project description:Transcriptional profiling of Candida albicans comparing fluconazole treated cells with fluconazole and osthole treated cells
2017-04-24 | GSE84936 | GEO
Project description:Purpose: Compare the fluconazole-induced transcriptome of isogenic wild-type and upc2A null cells. Methods: Prepare total RNA from wild-type and upc2A null cells grown under unstressed conditions or challenged with 50 microgram/ml fluconazole for 6 hours. Use standard RNA-seq to evaluate and compare the transcriptomic changes caused by fluconazole in the presence or absence of UPC2A. Results: These data established that over 100 genes were induced by fluconazole in a UPC2A-dependent manner. However, most fluconazole-induced genes (>500) did not require the presence of UPC2A. Fluconazole-induced genes included the expected genes involved in ergosterol biosynthesis but also large number of plasma membrane-localized transporters. Conclusions: These data suggest that Upc2A provided transcriptional co-regulation between membrane transporters and the lipid environment in which these proteins function. A significant portion of the fluconazole-induced transcriptome does not require the presence of Upc2A, suggesting the presence of other transcriptional circuits responsive to this pharmacologic block of ergosterol biosynthesis.
2021-09-23 | GSE182489 | GEO
Project description:Transcriptional profiling of Candida albicans comparing fluconazole treated cells with fluconazole- and berberine-treated cells, as well untreated cells with berberine treated cells
2013-11-14 | GSE43662 | GEO
Project description:Fungal infections are an emerging health risk, especially those involving yeast that are resistant to antifungal agents. To understand the range of mechanisms by which yeasts can respond to anti-fungals, we compared gene expression patterns across three evolutionarily distant species - Saccharomyces cerevisiae, Candida glabrata and Kluyveromyces lactis - over time following fluconazole exposure. Conserved and diverged expression patterns were identified using a novel soft clustering algorithm that concurrently clusters data from all species while incorporating sequence orthology. The analysis suggests complementary strategies for coping with ergosterol depletion by azoles - Saccharomyces imports exogenous ergosterol, Candida exports fluconazole, while Kluyveromyces does neither leading to extreme sensitivity. In support of this hypothesis we find that only Saccharomyces becomes more azole resistant in ergosterol-supplemented media; that this depends on sterol importers Aus1 and Pdr11; and that transgenic expression of sterol importers in Kluyveromyces alleviates its drug sensitivity. We have compared the dynamic transcriptional responses of three diverse yeast species to fluconazole treatment using a novel clustering algorithm. This approach revealed significant divergence among regulatory programs associated with fluconazole sensitivity. In future, such approaches might be used to survey a wider range of species, drug concentrations and stimuli to reveal conserved and divergent molecular response pathways. There are three yeast species being studied. Each species has three biological replicates. Each biological replicate has 6 time points (0,1/3,2/3,1,2,4). These time points are combined in equal proportions to form a species and replicate specific “Reference Pool”. Each time point (except time 0) is compared against the Reference Pool. We also perform dye-swapped technical replicates for each biological replicate.
2010-07-08 | E-GEOD-15710 | biostudies-arrayexpress