Ontology highlight
ABSTRACT:
PROVIDER: PRJNA664881 | ENA |
REPOSITORIES: ENA
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Project description:Fungal infections have become a clinical challenge due to the emergence of drug-resistance of invasive fungi and a rapid increase of novel pathogens. The development of drug resistance has further restricted the use of antifungal agents. Therefore, there is anurgentneedto searchforalternativetreatmentoptions for Cryptococcus neoformans (C. neoformans). Disulfiram (DSF) has a high human safety profile and promising applications as an antiviral, antifungal, antiparasitic, and anticancer agent. In contrast, the effect of DSF on Cryptococcus has yet to be thoroughly researched. This study investigated the antifungal effect and mechanism of DSF againstC. neoformansto provide a new theoretical foundation for treating Cryptococcal infections. In vitro studies demonstrated that DSF inhibitedCryptococcusat minimum inhibitory concentrations (MICs) ranging from 1.0 to 8.0 μg/mL. Combined antifungal effects were also observed with 5-fluorocytosine, amphotericin B, terbinafine, or ketoconazole. In vivo, DSF exerted asignificantprotectiveeffectforGalleria mellonella infected with C. neoformans.Mechanistic investigations showed that DSF dose-dependently inhibited the melanin, urease, acetaldehyde dehydrogenase, capsule, and biofilm formation or viability ofC. neoformans.Further study indicated DSF affectedC. neoformansby interfering with multiple biological pathways, including replication, metabolism, membrane transport, and biological enzyme activity. Potentially essential targets of these pathways included acetaldehyde dehydrogenase, catalase, ATP-binding cassette transporter (ABC transporter) AFR2, and iron-sulfur cluster transporter ATM1. These findings contribute to the understanding of mechanisms inC. neoformans, and provide new insights for the application of DSF.
2023-12-31 | GSE248987 | GEO
Project description:New antifungal drugs are urgently needed due to the currently limited selection, the emergence of drug resistance, and the toxicity of several commonly used drugs. To identify drug leads, we screened small molecules using a Saccharomyces reporter bioassay in which the yeast heterologously expresses Hik1, a group III hybrid histidine kinase (HHK) from Magnaporthe grisea. Group III HHKs are integral in fungal cell physiology, and highly conserved throughout this kingdom; they are absent in mammals, making them an attractive drug target. Our screen identified compounds 13 and 33, which showed robust activity against numerous fungal genera including Candida, Cryptococcus and molds such as Aspergillus and Rhizopus. Drug-resistant Candida from patients were also highly susceptible to compounds 13 and 33. While the compounds do not act directly on HHKs, microarray analysis showed that compound 13 induced transcripts associated with oxidative stress, and compound 33, transcripts linked with heavy metal stress. Both compounds were highly active against Candida biofilm, in vitro and in vivo, and exerted synergy with fluconazole, which was inactive alone. Thus, we identified potent, broad-spectrum antifungal drug leads from a small molecule screen using a high-throughput, yeast reporter bioassay. Two-color experimental design testing the effects of 2 antifungal compounds (13 and 33) after 0, 20, 40 60 min. In the referred publication, the t=20, 40, 60 data was normalized against the t=0 data
2012-04-30 | E-GEOD-35105 | biostudies-arrayexpress
Project description:Invasive fungal infections (IFIs) are difficult to treat. Few effective antifungal drugs are available and many have problems with toxicity, efficacy and drug-resistance. To overcome these challenges, existing therapies may be enhanced using more than one agent acting in synergy. Previously, we have found amphotericin B (AMB) and the iron chelator, lactoferrin (LF), were synergistic against Cryptococcus neoformans and Saccharomyces cerevisiae. This study investigates the mechanism of AMB+LF synergy using RNA-seq in Cryptococcus neoformans H99.
2019-09-08 | GSE130375 | GEO
Project description:New antifungal drugs are urgently needed due to the currently limited selection, the emergence of drug resistance, and the toxicity of several commonly used drugs. To identify drug leads, we screened small molecules using a Saccharomyces reporter bioassay in which the yeast heterologously expresses Hik1, a group III hybrid histidine kinase (HHK) from Magnaporthe grisea. Group III HHKs are integral in fungal cell physiology, and highly conserved throughout this kingdom; they are absent in mammals, making them an attractive drug target. Our screen identified compounds 13 and 33, which showed robust activity against numerous fungal genera including Candida, Cryptococcus and molds such as Aspergillus and Rhizopus. Drug-resistant Candida from patients were also highly susceptible to compounds 13 and 33. While the compounds do not act directly on HHKs, microarray analysis showed that compound 13 induced transcripts associated with oxidative stress, and compound 33, transcripts linked with heavy metal stress. Both compounds were highly active against Candida biofilm, in vitro and in vivo, and exerted synergy with fluconazole, which was inactive alone. Thus, we identified potent, broad-spectrum antifungal drug leads from a small molecule screen using a high-throughput, yeast reporter bioassay.
2012-05-01 | GSE35105 | GEO
Project description:Antagonism between two mechanisms of antifungal drug resistance
| PRJNA94857 | ENA
Project description:Following antifungal treatment, Candida albicans, and other human pathogenic fungi can undergo microevolution, which leads to the emergence of drug resistance. However, the capacity for microevolutionary adaptation of fungi goes beyond the development of drug resistance. Here we used an experimental microevolution approach to show that one of the central pathogenicity mechanisms of C. albicans, the yeast-to-hyphae transition, can be subject to experimental evolution. The C. albicans cph1?/efg1? mutant is non-filamentous, as central signalling pathways linking environmental cues to hypha formation are disrupted. We subjected this mutant to constant selection pressure in the hostile environment of the macrophage phagosome. In a comparatively short time-frame, the mutant evolved the ability to escape macrophages by filamentation. To investigate the transcriptional response underlying the yeast-to-filament transition in the evolved strain, we applied RNA-Seq technology. Furthermore, RNA-Seq data were used to identify SNPs, which are specific for the evolved strain. For both strains, the cph1?/efg1? mutant and the Evo-strain, two conditions, one promotes yeast growth the other filamentous growth, were investigated. For each condition three biological replicates were analysed.
2015-03-31 | E-GEOD-56174 | biostudies-arrayexpress
Project description:Two mutant strains of Aspergillus fumigatus derived from strain A1160, HapB and 29.9, display resistance to the antifungal drug itraconazole. To understand what underlying transcriptional processes contribute to this resistance, A1160, HapB and 29.9 were cultured either in the presence or absence of itraconazole. RNA-sequencing was used to compare transcription profiles of each mutant strain with or without the drug, to A1160 with or without drug.
2016-04-30 | E-SYBR-5 | biostudies-arrayexpress
Project description:The clinical response to chemotherapy regimen of cisplatin and paclitaxel in lung adenocarcinoma is frequently limited in magnitude and duration due to drug resistance. Recently, epithelial-mesenchymal transition (EMT) was associated with drug resistance. However, the underlying mechanisms remain elusive. To discover mechanisms of resistance, we developed the epithelial-like and mesenchymal-like A549 cell lines (lung adenocarcinoma cell line), and have their lncRNA expressions profiled and compared. Results provide insight into the molecular mechanisms underlying chemotherapy-resistance.
2019-12-31 | GSE129439 | GEO
Project description:Following antifungal treatment, Candida albicans, and other human pathogenic fungi can undergo microevolution, which leads to the emergence of drug resistance. However, the capacity for microevolutionary adaptation of fungi goes beyond the development of drug resistance. Here we used an experimental microevolution approach to show that one of the central pathogenicity mechanisms of C. albicans, the yeast-to-hyphae transition, can be subject to experimental evolution. The C. albicans cph1Δ/efg1Δ mutant is non-filamentous, as central signalling pathways linking environmental cues to hypha formation are disrupted. We subjected this mutant to constant selection pressure in the hostile environment of the macrophage phagosome. In a comparatively short time-frame, the mutant evolved the ability to escape macrophages by filamentation. To investigate the transcriptional response underlying the yeast-to-filament transition in the evolved strain, we applied RNA-Seq technology. Furthermore, RNA-Seq data were used to identify SNPs, which are specific for the evolved strain.
2015-03-31 | GSE56174 | GEO
Project description:Bladder cancer has a high incidence worldwide accompanies by high recurrent rate after treatment. The emergence of primary or acquired chemotherapy resistance leads to poor efficacy in many cases. Therefore, there is an urgent need to elucidate the mechanism underlying drug resistance and enhance the sensitivity of cancer cells to chemotherapy. To explore the underlying mechanisms of drug resistance, we firstly established a drug-resistant cell model T24/THP by repeated exposure of T24 cells to pirarubicin (THP) whose concentration increases gradually. After a stable mode of drug resistance of cancer cell had been repeatedly tested, we performed a gene expression profiling by microarray.
2024-11-01 | GSE188769 | GEO