Candida albicans
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ABSTRACT:
PROVIDER: PRJNA272618 | ENA |
REPOSITORIES: ENA
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Project description:Fungal infections are a serious health problem in clinics especially in the immune-compromised patient. Disease ranges from widespread superficial infections like vulvovaginal infections to life-threatening systemic candidiasis. Especially for systemic mycoses only a limited arsenal of antifungals is available. The most commonly used classes of antifungal compounds used include azoles, polyenes and echinocandines. Due to emerging resistance to standard therapy and significant side effects and high costs for several antifungals.,there is a medical need for new antifungals in the clinic and general practice. In order to expand the arsenal of compounds with antifungal activities we previously screened a compound library, using a new type of activity-selectivity (AS) assay analysing both the antifungal activity and the compatibility with human cells at the same time. One compound, ((S)-2-(1-aminoisobutyl)-1-(3-chlorobenzyl) benzimidazole (EMC120B12)), showed high antifungal activity against several species of pathogenic yeasts including C. glabrata and C. krusei, species which are highly refractory to antifungals, especially to the commonly used azoles. Here we could show by transcriptional profiling and sterol analysis that the target of this new antifungal compound is the ergosterol pathway. The effects of EMC120B12 on sterol biosynthesis mimic those of fluconazole, strongly indicating that EMC120B12 also targets ERG11 like the azols. But not only the marker sterol 14 methylergosta 8,24(28) dien 3β,6α diol accumulated in C. krusei under EMC120B12 treatment, but also hitherto unknown related sterols. The novel sterols have a 3β,6α diol structure. Furthermore, this is the first time that a benzimidazole structure has been shown to result in a block of the sterol pathway by accumulating marker sterols connected to ERG11 inactivation. In total, three biological replicates were performed. All experiments were performed as dye swaps. Thus, in total 18 arrays have been hybridzed. Hybridization experiments included an untreated reference sample and a sample of cells treated with either ((1S)-1-[1-(3-chlorobenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl-amine) (EMC120B12), Fluconazole or Nocodazole. The array included one technical replicate of each probe.
2015-06-30 | E-GEOD-64976 | biostudies-arrayexpress
Project description:Fungal infections are a serious health problem in clinics especially in the immune-compromised patient. Disease ranges from widespread superficial infections like vulvovaginal infections to life-threatening systemic candidiasis. Especially for systemic mycoses only a limited arsenal of antifungals is available. The most commonly used classes of antifungal compounds used include azoles, polyenes and echinocandines. Due to emerging resistance to standard therapy and significant side effects and high costs for several antifungals.,there is a medical need for new antifungals in the clinic and general practice. In order to expand the arsenal of compounds with antifungal activities we previously screened a compound library, using a new type of activity-selectivity (AS) assay analysing both the antifungal activity and the compatibility with human cells at the same time. One compound, ((S)-2-(1-aminoisobutyl)-1-(3-chlorobenzyl) benzimidazole (EMC120B12)), showed high antifungal activity against several species of pathogenic yeasts including C. glabrata and C. krusei, species which are highly refractory to antifungals, especially to the commonly used azoles. Here we could show by transcriptional profiling and sterol analysis that the target of this new antifungal compound is the ergosterol pathway. The effects of EMC120B12 on sterol biosynthesis mimic those of fluconazole, strongly indicating that EMC120B12 also targets ERG11 like the azols. But not only the marker sterol 14 methylergosta 8,24(28) dien 3β,6α diol accumulated in C. krusei under EMC120B12 treatment, but also hitherto unknown related sterols. The novel sterols have a 3β,6α diol structure. Furthermore, this is the first time that a benzimidazole structure has been shown to result in a block of the sterol pathway by accumulating marker sterols connected to ERG11 inactivation.
2015-06-30 | GSE64976 | GEO
Project description:Response of Candida albicans towards a novel antifungal benzimidazole derivative
| PRJNA127111 | ENA
Project description:Biomaterial infections are an increasingly alarming problem, and because of their intrinsic recalcitrance to conventional therapy, a new class of antifungal drugs must be explored. 10b, a 2-aminotetralin derivate, was synthesized as a novel chemical structural antifungal agent and exibited strong anti-biofilm activity. To further investigate the action mechanism, we used microarray analysis to investigate the genes expression profiles of C. albicans biofilms treated or untreated with 10b and found 150 genes were differentially expressed. Of them, 69 showed a decrease in expression and 81 showed an increase in expression -10 differentially expressed genes related to biofilm formation, Filamentous or hypha growth. A gene related to specifically hydrolyzing β-1, 3 glucan was significantly increased. 10 down-regulated genes were involved in glycolysis, fermentation and active oxygen scavenging. 15 overexpressed genes were related to the lipid metabolic process. Of them, 13 genes were directly linked to ergosterol biosynthesis including ERG2, ERG6 and ERG11. 10 genes related to translation were over-expressed. Among them, 2 genes involved in negative regulation of transcription were significantly up-regulated.
2009-12-10 | GSE19226 | GEO
Project description:In depth characterization of the activity of a novel synthetic macrocyclic antifungal compound
| PRJNA273876 | ENA
Project description:Azole resistance and varying degrees of cross-resistance to other members of the azole family in clinical isolates have been documented, which has necessitated additional and prolonged use of the antifungal agents available. 2-Amino-Nonyl-6-Methoxyl-Tetralin Muriate (10b), a novel chemical structural aminotetralin derivate, is synthesized as an antifungal agent and exibited strong antifungal activity. To further investigated the action mechanism, we used microarray analysis to investigate the genes expression profiles of C. albicans cells treated or untreated with 10b and found 957 genes were differentially expressed. Of them,457 showed a decrease in expression and 500 showed an increase in expression. 33 down-regulated genes were involved in glycolysis (e.g., PFK1, CDC19 and HXK2), fermentation (e.g., PDC11, ALD5 and ADH1) and respiratory electron transport chain (e.g., CBP3, COR1 and QCR8). 30 differentially expressed genes were found to relate to biofilm formation, filamentous or hyphal growth. It was noticed that striking up-regulation of SFL1 and marked down-regulation of YWP1 directly related to prevent C. albicans from changing its morphology from the yeast form to the hyphal. Two genes related to specifically hydrolyzing beta-1, 3 glucan (e.g., XOG1) and chitin (e.g., CHT1) were significantly increased. 40 overexpressed genes and 15 down-regulated genes were related to the lipid metabolic process. Of them, Eight were directly linked to ergosterol biosynthesis, including ERG2, ERG6 and ERG11. 99 genes related to translation were down-regulated following exposure to 10b, which account for 21.66% in down-regulated genes. This suggested that translation might be lower in SC5314 cells exposed to 10b than in control.
2011-05-11 | GSE19552 | GEO
Project description:Biomaterial infections are an increasingly alarming problem, and because of their intrinsic recalcitrance to conventional therapy, a new class of antifungal drugs must be explored. 10b, a 2-aminotetralin derivate, was synthesized as a novel chemical structural antifungal agent and exibited strong anti-biofilm activity. To further investigate the action mechanism, we used microarray analysis to investigate the genes expression profiles of C. albicans biofilms treated or untreated with 10b and found 150 genes were differentially expressed. Of them, 69 showed a decrease in expression and 81 showed an increase in expression -10 differentially expressed genes related to biofilm formation, Filamentous or hypha growth. A gene related to specifically hydrolyzing β-1, 3 glucan was significantly increased. 10 down-regulated genes were involved in glycolysis, fermentation and active oxygen scavenging. 15 overexpressed genes were related to the lipid metabolic process. Of them, 13 genes were directly linked to ergosterol biosynthesis including ERG2, ERG6 and ERG11. 10 genes related to translation were over-expressed. Among them, 2 genes involved in negative regulation of transcription were significantly up-regulated. Total RNA from the control SC5314 biofilms and 10b-treated SC5314 biofilms were used to generate target cDNA, and then hybridized to 8k Candida albicans Genome Array Genechips, representing about 7925 characterized Candida albicans genes. Two independent experiments were conducted. Reference strain was control SC5314 biofilms and test strain was SC5314 biofilms treated with 10b.
2010-05-18 | E-GEOD-19226 | biostudies-arrayexpress
Project description:Azole resistance and varying degrees of cross-resistance to other members of the azole family in clinical isolates have been documented, which has necessitated additional and prolonged use of the antifungal agents available. 2-Amino-Nonyl-6-Methoxyl-Tetralin Muriate (10b), a novel chemical structural aminotetralin derivate, is synthesized as an antifungal agent and exibited strong antifungal activity. To further investigated the action mechanism, we used microarray analysis to investigate the genes expression profiles of C. albicans cells treated or untreated with 10b and found 957 genes were differentially expressed. Of them,457 showed a decrease in expression and 500 showed an increase in expression. 33 down-regulated genes were involved in glycolysis (e.g., PFK1, CDC19 and HXK2), fermentation (e.g., PDC11, ALD5 and ADH1) and respiratory electron transport chain (e.g., CBP3, COR1 and QCR8). 30 differentially expressed genes were found to relate to biofilm formation, filamentous or hyphal growth. It was noticed that striking up-regulation of SFL1 and marked down-regulation of YWP1 directly related to prevent C. albicans from changing its morphology from the yeast form to the hyphal. Two genes related to specifically hydrolyzing beta-1, 3 glucan (e.g., XOG1) and chitin (e.g., CHT1) were significantly increased. 40 overexpressed genes and 15 down-regulated genes were related to the lipid metabolic process. Of them, Eight were directly linked to ergosterol biosynthesis, including ERG2, ERG6 and ERG11. 99 genes related to translation were down-regulated following exposure to 10b, which account for 21.66% in down-regulated genes. This suggested that translation might be lower in SC5314 cells exposed to 10b than in control. Total RNA from the control SC5314 cells and 10b-treated SC5314 cells were used to generate target cDNA, and then hybridized to 8k Candida albicans Genome Array Genechips, representing about 7925 characterized Candida albicans genes. Two independent experiments were conducted. Reference strain was control SC5314 cells and test strain was SC5314 cells treated with 10b.
2011-05-11 | E-GEOD-19552 | biostudies-arrayexpress
Project description:To investigate the mode of action of a novel class of antifungal synthtic acrylamide peptides, the pathogenic yeast, Candida albicans, was exposed to sublethal doses of peptides with different structures. The experiments include the most effective structure, LH, peptides with no antifungal effects (HEAm) and intermediates as well as controls.
2024-06-18 | E-MTAB-13294 | biostudies-arrayexpress
Project description:In Candida albicans, Upc2 is a zinc-cluster transcription factor that targets genes including those of the ergosterol biosynthesis pathway. To date there have been three documented UPC2 gain-of-function (GOF) mutations recovered from fluconazole-resistant clinical isolates that contribute to an increase in ERG11 expression and decreased fluconazole susceptibility. In a group of 62 fluconazole-resistant isolates, we found that 47 of these overexpressed ERG11 by at least two-fold over that of an average expression of 3 unrelated fluconazole susceptible strains. Of those 47 isolates, 29 contained a mutation in UPC2, whereas the remaining 18 isolates did not. Of the isolates containing mutations in UPC2, we recovered eight distinct mutations resulting in single putative amino acid substitutions: G648D, G648S, A643T, A643V, Y642F, G304R, A646V and W478C. Seven of these resulted in increased ERG11 expression, increased cellular ergosterol, and decreased susceptibility to fluconazole as compared to the wild-type strain. Genome-wide transcriptional analysis was performed for the four strongest Upc2 amino acid substitutions (A643V, G648D, G648S and Y642F). Genes commonly upregulated in all four mutations included those involved in ergosterol biosynthesis, in oxidoreductase activity, the major facilitator efflux pump encoded by the MDR1 gene, and the uncharacterized ATP binding cassette transporter CDR11. These findings demonstrate that gain-of-function mutations in UPC2 are more prevalent than previously thought among clinical isolates, make a significant contribution to azole antifungal resistance, but do not account for ERG11 overexpression in all such isolates of C. albicans.
2013-01-31 | GSE39201 | GEO