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In depth characterization of the activity of a novel synthetic macrocyclic antifungal compound

ABSTRACT: The systemic infections by peptogenous fungi member of the genera Candida and Aspergillus represent a serious threat for public health. During previous research we have successfully identified a family of compounds active against different Candida spp. including strains resistant to antifungal drugs currently on the market. We have further refined our knowledge on this field by identifying a possible molecular target that could justify the activity of these compounds. The research of the mode of action of the compounds object of this manuscript was supported also by fluorescent microscopy of labeled derivatives. Transcriptional data indicates that one of the macrocyclic antifungal induces a drug response involving ATP binding cassette transporters. Moreover the data show that the macrocyclic antifungal decrease expression of cell wall biosynthesis genes. Moreover, the quality of the compounds and their potential was tested in vivo revealing a promising profile in particular against fungal infection caused by resistant strains

ORGANISM(S): Candida albicans

PROVIDER: GSE65396 | GEO | 2015/04/01

SECONDARY ACCESSION(S): PRJNA273876

REPOSITORIES: GEO

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In depth characterization of the activity of a novel synthetic macrocyclic antifungal compound

Project description:The systemic infections by peptogenous fungi member of the genera Candida and Aspergillus represent a serious threat for public health. During previous research we have successfully identified a family of compounds active against different Candida spp. including strains resistant to antifungal drugs currently on the market. We have further refined our knowledge on this field by identifying a possible molecular target that could justify the activity of these compounds. The research of the mode of action of the compounds object of this manuscript was supported also by fluorescent microscopy of labeled derivatives. Transcriptional data indicates that one of the macrocyclic antifungal induces a drug response involving ATP binding cassette transporters. Moreover the data show that the macrocyclic antifungal decrease expression of cell wall biosynthesis genes. Moreover, the quality of the compounds and their potential was tested in vivo revealing a promising profile in particular against fungal infection caused by resistant strains Gene expression was measured in Candida albians CAF2-1 exposed to the macrocyclic compound FR59 at 3 µM at two time points (15 min and 45 min), The one-color system was used. Three independent experiments were performed using non-exposed cells, 15 min and 45 min exposed cells.

2015-04-01 | E-GEOD-65396 | biostudies-arrayexpress

Identification and characterization of potent, broad-spectrum antifungal compounds using a yeast reporter bioassay.

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

Identification and characterization of potent, broad-spectrum antifungal compounds using a yeast reporter bioassay.

2012-05-01 | GSE35105 | GEO

RNA sequencing of the treatment of Aspergillus fumigatus with the new antifungal drug 089 -SYBARIS

Project description:The mechanism of action of the new antifungal compound 089 was identified in Saccharomyces cerevisiae. The compound had antifungal effects also on pathogenic fungi. While on Candida species the treatment induced cells death, on A. fumigatus strains it inhibited the conidia transition to hyphae. We carried out RNA sequencing analysis to evaluate at the molecular level the effect of the treatment on Aspergillus.

2020-03-04 | E-MTAB-5309 | biostudies-arrayexpress

In vitro antifungal activity of myriocin against drug-resistant Candida auris strains

Project description:In vitro antifungal activity of myriocin against drug-resistant Candida auris strains

| PRJNA678875 | ENA

In vitro antifungal activity of myriocin against drug-resistant Candida auris strains

Project description:Myriocin exhibited very low MIC values (0.016 to 0.4 mg/L) to all C. auris isolates including several multidrug-resistant strains. The yeast-form, filamentous, or aggregating-form cells were all susceptible to the chemical. The antifungal effect was majorly due to the fungistatic activity, although an extended treatment could lead to the fungicidal activity to C. auris cells. Transcriptomic analysis demonstrates that myriocin suppresses the cellular metabolic activity and induces the expression of stress or antifungal response genes.

2020-12-03 | GSE161599 | GEO

Transcriptome profile of tra1 mutant in C. albicans in response to the antifungal caspofungin

Project description:The emergence of drug-resistant fungal strains is a threat to human health. Identifying targets that increase the susceptibility of fungal pathogens to current therapies will significantly improve outcomes. Tra1 is an essential component of the SAGA and NuA4 transcriptional co-activator complexes and is linked to multiple cellular processes associated with the yeast response to antifungal drugs. This submission contains RNA sequencing data from Candida albicans strain expressing a Tra1 mutant with three arginine to glutamine mutations in the PI3K domain (tra1Q3; Berg et al., 2018) treated with or without the antifungal caspofungin. Our goal was to identify genes regulated by Tra1 in C. albicans and identify genes with differential responses in the mutant tra1 strain upon capsofungin relative to the wild-type strain. We identified 68 genes that were differentially expressed when the tra1Q3 strain was treated with caspofungin, as compared to gene expression changes induced by either tra1Q3 or caspofungin alone. Included in this set were genes involved in cell wall maintenance, adhesion and filamentous growth. As a critical component of both SAGA and NuA4, Tra1 is uniquely positioned to regulate the yeast antifungal response and emerges, through targeting its PI3K domain, as a promising new therapeutic target for fungal infections.

2021-03-17 | GSE168988 | GEO

Microarray of Candida albicans treated with sublethal concentrations of the antifungal Jagaricin

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

Mistranslation accelerates the evolution of antifungal drug resistance in Candida albicans [CGH]

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 | GSE60120 | GEO

Mistranslation accelerates the evolution of antifungal drug resistance in Candida albicans [Gene expression]

2017-07-18 | GSE60121 | GEO

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