Gene expression response to the antifungal compound 6-Nonadecynoic acid (6-NDA) in Saccharomyces cerevisiae and Candida albicans
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PROVIDER: PRJNA152529 | ENA |
REPOSITORIES: ENA
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Project description:6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model organism Saccharomyces cerevisiae to investigate the mechanism of action of this compound. 6-NDA elicited a transcriptome response indicative of fatty acid stress, altering the expression of genes known to be affected when yeast cells are grown in the presence of oleate. Mutants of S. cerevisiae lacking transcription factors that regulate fatty acid beta-oxidation showed increased sensitivity to 6-NDA. Fatty acid profile analysis indicated that 6-NDA inhibited the formation of fatty acids longer than 14 carbons in length. In addition, the growth inhibitory effect of 6-NDA was rescued in the presence of exogenously supplied oleate. To investigate the response of a pathogenic fungal species to 6-NDA, transcriptional profiling and biochemical analyses were also conducted in C. albicans. The transcriptional response and fatty acid profile of C. albicans were comparable to those obtained in S. cerevisiae, and the rescue of growth inhibition with exogenous oleate was also observed in C. albicans. In addition, 6-NDA enhanced the potency of the antifungal drug fluconazole in a fluconazole-resistant clinical isolate of C. albicans. Collectively, our results indicate that the antifungal activity of 6-NDA is mediated by a disruption in fatty acid homeostasis, and that this compound has potential utility in combination therapy in the treatment of drug-resistant fungal infections.
2012-02-08 | GSE35604 | GEO
Project description:Candida albicans were treated with a sublethal concentration of the antifungal Jagaricin for either a short time (30 min) or until an OD of 0.5 (indicating log growth) was reached. Controls were grown without any antifungal to determine cellular reactions to the compound.
2019-06-14 | E-MTAB-7718 | biostudies-arrayexpress
Project description:6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model organism Saccharomyces cerevisiae to investigate the mechanism of action of this compound. 6-NDA elicited a transcriptome response indicative of fatty acid stress, altering the expression of genes known to be affected when yeast cells are grown in the presence of oleate. Mutants of S. cerevisiae lacking transcription factors that regulate fatty acid ?-oxidation showed increased sensitivity to 6-NDA. Fatty acid profile analysis indicated that 6-NDA inhibited the formation of fatty acids longer than 14 carbons in length. In addition, the growth inhibitory effect of 6-NDA was rescued in the presence of exogenously supplied oleate. To investigate the response of a pathogenic fungal species to 6-NDA, transcriptional profiling and biochemical analyses were also conducted in C. albicans. The transcriptional response and fatty acid profile of C. albicans were comparable to those obtained in S. cerevisiae, and the rescue of growth inhibition with exogenous oleate was also observed in C. albicans. In addition, 6-NDA enhanced the potency of the antifungal drug fluconazole in a fluconazole-resistant clinical isolate of C. albicans. Collectively, our results indicate that the antifungal activity of 6-NDA is mediated by a disruption in fatty acid homeostasis, and that this compound has potential utility in combination therapy in the treatment of drug-resistant fungal infections. Cultures of S. cerevisiae strain S288C were started at OD600 of 0.1, allowed to grow to OD600 of 0.2, then treated with either DMSO (0.25%) or 6-NDA at the IC50 concentration (2.2 ug/ml). When OD600 of 0.5 was reached, cells were harvested and frozen. Two biological replicate cultures were grown for each treatment, and RNA from each replicate was hybridized to 2 independent arrays, resulting in 4 hybridizations for each treatment. Cultures of C. albicans strain SC5314 were started at OD600 of 0.1, allowed to grow to OD600 of 0.2, then treated with either DMSO (0.25%) or 6-NDA at the IC50 concentration (4 ug/ml). When OD600 of 0.5 was reached, cells were harvested and frozen. Three biological replicate cultures were grown for each treatment, and RNA from each replicate was hybridized as dye-swap pairs, resulting in 6 hybridizations for each treatment.
2012-02-08 | E-GEOD-35604 | biostudies-arrayexpress
Project description:Sampangine, a plant-derived alkaloid found in the Annonaceae family, exhibits strong inhibitory activity against the opportunistic fungal pathogens Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. In the present study, transcriptional profiling experiments coupled with the analysis of mutants were performed in an effort to elucidate its mechanism of action. Using Saccharomyces cerevisiae as a model organism, we show that sampangine produces a transcriptional response indicative of hypoxia, altering the expression of genes known to respond to low oxygen conditions. Several additional lines of evidence obtained suggest that these responses could involve effects on heme. First, the hem1 deletion mutant lacking the first enzyme in the heme biosynthetic pathway showed increased sensitivity to sampangine, and exogenously supplied hemin partially rescued the inhibitory activity of sampangine in wild-type cells. In addition, heterozygous mutants with deletions in genes involved in five out of eight steps in the heme biosynthetic pathway showed increased susceptibility to sampangine. Furthermore, spectral analysis of pyridine extracts indicated significant accumulation of free porphyrins in sampangine-treated cells. Transcriptional profiling experiments were also performed in C. albicans to investigate the response of a pathogenic fungal species to sampangine. Taking into account the known differences in the physiological responses of C. albicans and S. cerevisiae to low oxygen, significant correlations were observed between the two transcription profiles suggestive of heme-related defects. Our results indicate that the antifungal activity of the plant alkaloid sampangine is due, at least in part, to perturbations in the biosynthesis or metabolism of heme. Keywords: antifungal compound, transcriptional profiling, C. albicans
2008-01-09 | GSE10075 | GEO
Project description:Human serum amyloid A (SAA) is a major acute phase protein and shows a massive increase of concentration in plasma during inflammation. In the current study, we report that recombinant human and mouse SAA1 (rhSAA1 and rmSAA1) have a potent antifungal activity against the major fungal pathogen Candida albicans. rhSAA1 binds to the cell surface of C. albicans and promotes cell aggregation. At high concentrations, rhSAA1 disrupts the membrane integrity and induces rapid cell death of C. albicans. Further investigation demonstrates that rhSAA1 targets on the cell wall adhesin Als3 of C. albicans. Inactivation of ALS3 in C. albicans leads to remarkably decreased cell aggregation and death upon rhSAA1 treatment, implying that Als3 plays a critical role in SAA1 sensing. Moreover, deletion of the ALS3 transcriptional regulators such as AHR1, BCR1, and EFG1 in C. albicans results in a similar effect on cell responses to that of the als3/als3 mutant upon rhSAA1 treatment. Global gene expression profiling analysis indicates that rhSAA1 has a remarkable impact on the expression of cell wall- and metabolism-related genes in C. albicans. Our finding of the antifungal activity of rhSAA1 against C. albicans expands the function of this protein and would provide new insights into the understanding of the host-Candida interaction during infections.
2019-09-01 | GSE128598 | GEO
Project description:Plakortide F acid (PFA), a marine-derived polyketide endoperoxide, exhibits strong inhibitory activity against the opportunistic fungal pathogens Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model organism Saccharomyces cerevisiae, to investigate the mechanism of action of this compound. PFA elicited a transcriptome response indicative of a Ca2+ imbalance, affecting the expression of genes known to be responsive to altered cellular calcium levels. Several additional lines of evidence obtained supported a role for Ca2+ in PFA's activity. First, mutants lacking calcineurin and various Ca2+ transporters including pumps (Pmr1 and Pmc1) and channels (Cch1 and Mid1) showed increased sensitivity to PFA. In addition, the calcineurin inhibitors FK506 and cyclosporine A strongly enhanced PFA activity in wild-type cells. Furthermore, PFA activated the transcription of a lacZ reporter driven by the calcineurin-dependent response element. Finally, elemental analysis indicated a significant increase in intracellular calcium levels in PFA-treated cells. Collectively, our results demonstrate that PFA mediates its antifungal activity by perturbing Ca2+ homeostasis, thus representing a potentially novel mechanism distinct from that of currently used antifungal agents. DNA microarray analysis of gene expression response to the antifungal compound plakortide F acid in yeast
2011-01-28 | GSE26925 | GEO
Project description:Candida albicans exposure to antifungal polymers
| PRJEB65085 | ENA
Project description:Sampangine, a plant-derived alkaloid found in the Annonaceae family, exhibits strong inhibitory activity against the opportunistic fungal pathogens Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. In the present study, transcriptional profiling experiments coupled with the analysis of mutants were performed in an effort to elucidate its mechanism of action. Using Saccharomyces cerevisiae as a model organism, we show that sampangine produces a transcriptional response indicative of hypoxia, altering the expression of genes known to respond to low oxygen conditions. Several additional lines of evidence obtained suggest that these responses could involve effects on heme. First, the hem1 deletion mutant lacking the first enzyme in the heme biosynthetic pathway showed increased sensitivity to sampangine, and exogenously supplied hemin partially rescued the inhibitory activity of sampangine in wild-type cells. In addition, heterozygous mutants with deletions in genes involved in five out of eight steps in the heme biosynthetic pathway showed increased susceptibility to sampangine. Furthermore, spectral analysis of pyridine extracts indicated significant accumulation of free porphyrins in sampangine-treated cells. Transcriptional profiling experiments were also performed in C. albicans to investigate the response of a pathogenic fungal species to sampangine. Taking into account the known differences in the physiological responses of C. albicans and S. cerevisiae to low oxygen, significant correlations were observed between the two transcription profiles suggestive of heme-related defects. Our results indicate that the antifungal activity of the plant alkaloid sampangine is due, at least in part, to perturbations in the biosynthesis or metabolism of heme. GSE10073: Gene expression response to the antifungal compound sampangine in S. cerevisiae GSE10075: Gene expression response to the antifungal compound sampangine in C. albicans Keywords: SuperSeries Refer to individual Series
2010-05-26 | E-GEOD-10104 | biostudies-arrayexpress
Project description:Plakortide F acid (PFA), a marine-derived polyketide endoperoxide, exhibits strong inhibitory activity against the opportunistic fungal pathogens Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model organism Saccharomyces cerevisiae, to investigate the mechanism of action of this compound. PFA elicited a transcriptome response indicative of a Ca2+ imbalance, affecting the expression of genes known to be responsive to altered cellular calcium levels. Several additional lines of evidence obtained supported a role for Ca2+ in PFA's activity. First, mutants lacking calcineurin and various Ca2+ transporters including pumps (Pmr1 and Pmc1) and channels (Cch1 and Mid1) showed increased sensitivity to PFA. In addition, the calcineurin inhibitors FK506 and cyclosporine A strongly enhanced PFA activity in wild-type cells. Furthermore, PFA activated the transcription of a lacZ reporter driven by the calcineurin-dependent response element. Finally, elemental analysis indicated a significant increase in intracellular calcium levels in PFA-treated cells. Collectively, our results demonstrate that PFA mediates its antifungal activity by perturbing Ca2+ homeostasis, thus representing a potentially novel mechanism distinct from that of currently used antifungal agents. DNA microarray analysis of gene expression response to the antifungal compound plakortide F acid in yeast S. cerevisiae S288C cells at OD 0.2 were treated with either plakortide F acid (PFA) at IC50 concentration (0.62 ug/ml), or solvent (0.25% DMSO), allowed to grow to OD 0.5, then harvested and frozen. Three biological replicate samples were analyzed for each treatment.
2011-01-28 | E-GEOD-26925 | biostudies-arrayexpress
Project description:In the light of the increasing occurrence of antifungal resistance, there is an urgent need to search for new therapeutic strategies to overcome this phenomenon. One of the applied approaches is the synthesis of small-molecule compounds showing antifungal properties. Here we present a continuation of the research on the recently discovered anti-Candida albicans agent 4-AN. Using next generation sequencing and transcriptional analysis, we revealed that the treatment of C. albicans with 4-AN can change the expression profile of a large number of genes. The highest up-regulation was observed in the case of genes involved in cell stress, while the highest down-regulation was shown for genes coding sugar transporters. Real-time PCR analysis revealed 4-AN mediated reduction of the relative expression of genes engaged in fungal virulence (ALS1, ALS3, BCR1, CPH1, ECE1, EFG1, HWP1, HYR1, and SAP1). The determination of the fractional inhibitory concentration index (FICI) showed that the combination of 4-AN with Amphotericin B is synergistic. Finally, flow cytometry analysis revealed that the compound induces mainly necrosis in Candida albicans cells.
2020-05-20 | GSE150837 | GEO