A novel compound exhibits potent anti-Candida albicans activity
Ontology highlight
ABSTRACT:
ORGANISM(S): Candida albicans SC5314
PROVIDER: GSE287552 | GEO | 2025/04/01
REPOSITORIES: GEO
Similar Datasets
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: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:Candida auris has emerged as a significant healthcare-associated pathogen, posing a serious challenge due to its multidrug-resistant nature. Given the pre-existing constraints in the discovery and provision of new antifungals, there is thus an urgent imperative to design effective strategies to tackle this pressing global concern. Here, we screened a chemical library and identified phenyl-carbohydrazide derivatives with potent activity against both C. auris and the most prevalent human fungal pathogen, C. albicans. SPB00525 (N'-(2,6-Dichlorophenyl)-5-nitro-2-furohydrazide) exhibited potent activity against different strains that were resistant to standard antifungals. Using drug-induced haploinsufficient profiling, transcriptomics and metabolomic analysis, we uncovered that Ole1, a ∆(9) fatty acid desaturase, is most likely the target of SPB00525. We also found that another SPB00525 analog, HTS06170 (N'-(2,6-Dichlorophenyl)-4-methyl-1,2,3-thiadiazole-5-carbohydrazide) had a superior antifungal activity against both C. auris and C. albicans. Both SPB00525 and HTS06170 act as antivirulence agents and inhibited the invasive hyphal growth and biofilm formation of C. albicans. SPB00525 and HTS06170 attenuated fungal damage to human enterocytes and ameliorate survival of Galleria mellonella larvae used as a model of systemic candidiasis. These data, suggest that inhibiting ∆(9) fatty acid desaturase activity represents a potential therapeutic approach for treating fungal infection caused by the superbug C. auris and the most prevalent human fungal pathogen, C. albicans.
2024-05-13 | GSE267057 | GEO
Project description:We investigated the antifungal mechanism of action (MOA) of compound NSC319726 against C. albicans SC5314. We used transcriptome analysis of wild type C. albicans treated or not with compound. Exponentially growing cells were treated for 60 min with 4 μg/ml of NSC319726.
2017-11-04 | GSE106486 | GEO
Project description:Fungal infections are a serious health problem in the clinic especially in the immunocompromised patient. Disease ranges from widespread superficial vulvovaginal infections to life-threatening systemic candidiasis. Especially for systemic mycoses only a limited arsenal of antimycotica are available, including azoles, polyenes, echinocandines and amphothericin B. Due to emerging resistance to standard therapy and significant side effects for some antimycotica 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 screened compound libraries, including combinatorial libraries as well as more than 30 000 pure compounds derived from organic synthesis for antimycotic activity. In total more than 100 000 compounds were screened using an innovative AS (activity-selectivity) assay analyzing both the antifungal activity and the compatability with human cells at the same time. One promising hit, a Benzimidazol-2-yl-alkylamine derivative, was developed in a series of lead compounds showing potent antifungal activity. ((1S)-1-[1-(3-chlorobenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl-amine) (EMC120B12) showed the highest antifungal activity and best compatability with human cells in several cell culture models and against a number of different yeasts and clinical isolates. Transcriptional profiling indicates that the newly discovered compound is a potential inhibitor of the ergosterol-pathway.
2011-07-15 | GSE21622 | GEO
Project description:Candida spp. represent the third most frequent worldwide cause of infection in Intensive Care Units (ICUs) with a mortality rate of almost 40%. The classes of antifungals currently available include azoles, polyenes, echinocandins, pyrimidine derivatives, and allylamines. However, the therapeutical options for the treatment of candidiasis are drastically reduced by the increasing antifungal resistance. The growing need of a more targeted antifungal therapy is limited by the concern of finding molecules that specifically recognize the microbial cell without damaging the host. Epigenetic writers and erasers have emerged as promising targets in different contexts, including the treatment of fungal infections. In C. albicans, Hst3p, a sirtuin that deacetylates histone H3K56ac, represents an attractive antifungal target as it is essential for the fungus viability and virulence. Although the relevance of such epigenetic regulator is documented for the development of new antifungal therapies, the molecular mechanism behind Hst3p-mediated epigenetic regulation remains unrevealed. Here, we provide the first genome-wide profiling of H3K56ac in C. albicans; H3K56ac enriched regions are associated with Candida sp. pathogenicity. Upon Hst3p inhibition, 447 regions gain H3K56ac. Importantly, these genomic areas contain genes encoding for adhesin proteins, degradative enzymes, and white-opaque switch. Moreover, our RNA-seq analysis revealed 1330 upregulated and 1081 downregulated transcripts upon Hst3p inhibition, and among them, 87 genes whose transcription upregulation correlates well with changes in promoter H3K56 acetylation, including some well-known regulators of phenotypic switching and virulence, confirming that Hst3p is an appealing target for the development of new potential antifungal target.
2023-02-04 | E-MTAB-12167 | biostudies-arrayexpress
Project description:Fungal infections are a serious health problem in the clinic especially in the immunocompromised patient. Disease ranges from widespread superficial vulvovaginal infections to life-threatening systemic candidiasis. Especially for systemic mycoses only a limited arsenal of antimycotica are available, including azoles, polyenes, echinocandines and amphothericin B. Due to emerging resistance to standard therapy and significant side effects for some antimycotica 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 screened compound libraries, including combinatorial libraries as well as more than 30 000 pure compounds derived from organic synthesis for antimycotic activity. In total more than 100 000 compounds were screened using an innovative AS (activity-selectivity) assay analyzing both the antifungal activity and the compatability with human cells at the same time. One promising hit, a Benzimidazol-2-yl-alkylamine derivative, was developed in a series of lead compounds showing potent antifungal activity. ((1S)-1-[1-(3-chlorobenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl-amine) (EMC120B12) showed the highest antifungal activity and best compatability with human cells in several cell culture models and against a number of different yeasts and clinical isolates. Transcriptional profiling indicates that the newly discovered compound is a potential inhibitor of the ergosterol-pathway. In total, three biological replicates were performed. All experiments were performed as dye swaps. Thus, in total six arrays have been hybridzed. Hybridization experiments included an untreated reference sample and a sample of cells treated with ((1S)-1-[1-(3-chlorobenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl-amine) (EMC120B12). The array included one technical replicate of each probe.
2011-07-14 | E-GEOD-21622 | biostudies-arrayexpress
Project description:The limited number of antifungals and the emergence of multidrug-resistant Candida auris pose a significant challenge to human medicine. Here, we utilized combinatorial drug therapy as an approach to augment the activity of current azole antifungals against C. auris. We evaluated the fluconazole chemosensitization activity of 1547 FDA-approved drugs and clinical molecules against an azole-resistant strain of C. auris. This led to the discovery that lopinavir, an antiviral drug, is a potent agent capable of sensitizing C. auris to the effect of azole antifungals. At a therapeutically achievable concentration (4-8 µg/ml), lopinavir exhibited potent synergistic interactions with azole drugs, particularly with itraconazole, against C. auris (ΣFICI ranged from 0.05-0.50). The lopinavir/itraconazole combination enhanced the survival rate of C. auris-infected Caenorhabditis elegans by 90% and reduced the fungal burden in infected nematodes by 88.5% (p < 0.05). Moreover, lopinavir enhanced the antifungal activity of itraconazole against other medically important Candida species including C. albicans, C. tropicalis, C. glabrata, C. tropicalis, and C. parapsilosis. Comparative transcriptomic profiling revealed that lopinavir interferes with glucose permeation and ATP synthesis. This compromises the function of the efflux pumps presents in C. auris enhancing sensitivity to azole antifungals, as demonstrated by Nile red efflux assays. This study presents lopinavir as a novel, potent and broad-spectrum azole chemosensitizing agent that warrants further investigation against recalcitrant Candida infections.
2020-10-06 | GSE148341 | GEO
Project description:Candida albicans is the major invasive fungal pathogen of humans, causing diseases ranging from superficial mucosal infections to disseminated, systemic infections which are often life threatening. Hematogenously disseminated candidiasis (HDC) has a 47% mortality rate despite current antifungal therapy. An increase in prevalence, as well as an increasing resistance to most of the clinically important antifungal therapies, provides a strong impetus to understand the molecular mechanisms of pathogenesis and the acquisition of drug resistance. This information holds promise to identify novel therapeutic targets. A complete and accurate characterization of how the transcriptome of C. albicans responds to its interaction with cells from the host is an absolute necessity to accomplish this goal. RNA-seq (deep-sequencing of cDNA) provides an unbiased method to define comprehensively and systematically the transcriptome of an organism. We propose a comprehensive characterization of the C. albicans transcriptome in two different human tissue culture models, using RNA-seq. Such a characterization will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. We performed a comprehensive characterization of the C. albicans transcriptome in two different murine models of candidiasis (HDC and oropharyngeal candidiasis (OPC)), and two different human tissue culture models, using RNA-seq. Because the two murine models accurately recapitulate the pathology that is observed in clinical cases of candidiasis, we are confident that gene expression levels will provide an accurate representation of what occurs during the course of an infection in humans. Such a characterization of the in vivo transcriptome will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. PRJNA211732 C. albicans strain SC5314 was used to infect mice in a murine model of systemic candidiasis as well as a murine model of oropharyngeal candidiasis. For the disseminated model, kidneys were harvested at 6 hours, 12 hours, 24 hours and 48 hours after infection. For the oropharyngeal model, tongues were harvest at 1 day, 2 days, 3 days, and 5 days after infection. Total RNA was extracted from all harvested tissues and subject to RNA-seq. We also tested 3 C. albicans mutants in the disseminated model. For the infections with the mutant strains, only 1 timepoint (24 hours post-infection) was analyzed.
2014-03-30 | E-GEOD-56092 | biostudies-arrayexpress