Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1096176 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28553515_1.fastq.gz | Fastqsanger.gz | |||
| SRR28553515_2.fastq.gz | Fastqsanger.gz | |||
| SRR28553516_1.fastq.gz | Fastqsanger.gz | |||
| SRR28553516_2.fastq.gz | Fastqsanger.gz | |||
| SRR28553517_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 6 |
Similar Datasets
Project description:The rise of drug-resistant fungal species, such as Candida auris, poses a serious threat to global health, with mortality rates exceeding 40% and resistance rates surpassing 90%. The limited arsenal of effective antifungal agents underscores the urgent need for novel strategies. Here, we systematically evaluate the role of histone H3 post-translational modifications in C. auris drug resistance, focusing on acetylation mediated by Gcn5 and Rtt109, and methylation mediated by Set1, Set2, and Dot1. Mutants deficient in these enzymes exhibit varying degrees of antifungal drug sensitivity. Notably, we discover that GCN5 depletion and the subsequent loss of histone H3 acetylation downregulates key genes involved in ergosterol biosynthesis and drug efflux, resulting in increased susceptibility to azoles and polyenes. Additionally, Gcn5 regulates cell wall integrity and echinocandin resistance through the calcineurin signaling pathway and transcription factor Cas5. In infection models using Galleria mellonella and immunocompromised mice, GCN5 deletion significantly reduces the virulence of C. auris. Furthermore, the Gcn5 inhibitor CPTH2synergizes with caspofungin in vitro and in vivo without notable toxicity. These findings highlight the critical role of Gcn5 in the resistance and pathogenicity of C. auris, positioning it as a promising therapeutic target for combating invasive fungal infections.
2025-04-05 | GSE293594 | GEO
Project description:Candida auris has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive fungal candidiasis, with resistance rarely observed among clinical isolates. However, C. auris possesses extraordinary resistant profiles against all available antifungal drugs, including AmB. In our pursuit of potential solutions, we conducted a screening of a panel of 727 FDA-approved drugs and identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB’s activity against C. auris. LNP also potentiates the antifungal activity of AmB against other medically important species of Candida and Cryptococcus. Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome bc1). This interaction increases oxidative stress within fungal cells. Our results demonstrated the critical role of an active respiratory function in the antifungal activity of LNP. Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (~98%) CFU reduction in the burden of C. auris in the kidneys. Our findings strongly advocate for a thorough and comprehensive evaluation of LNP as a cytochrome bc1 inhibitor for combating drug-resistant C. auris infections.
2024-03-13 | GSE244094 | GEO
Project description:Whole cell proteomics of pan-antifungal drug resistant and sensitive Candida auris
2025-07-14 | PXD048342 | Pride
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:Transcriptomic analysis of different Candida auris clinical isolates with distinct antifungal susceptibility profiles.
2021-01-30 | GSE165762 | GEO
Project description:Candida auris is an emerging multidrug-resistant human fungal pathogen often refractory to treatment by all classes of antifungal drugs. Amphotericin B (AmB) is a fungicidal drug that, despite its toxic side effects, remains a drug of choice for the treatment of drug-resistant fungal infections, including those caused by C. auris. However, the molecular mechanisms underlying AmB resistance are poorly understood. In this study, we present data that suggests membrane lipid alterations and chromatin modifications are critical processes that contribute to or cause adaptive AmB resistance in clinical C. auris isolates. To determine the plausible cause of increased AmB resistance, we performed RNA-seq of AmB-resistant and sensitive C. auris isolates. Remarkably, AmB-resistant strains show a pronounced enrichment of genes involved in lipid and ergosterol biosynthesis, adhesion, drug transport as well as chromatin remodeling. The transcriptomics data confirm increased adhesion and reduced lipid membrane permeability of AmB-resistant strains compared to the sensitive isolates. The AmB-resistant strains also display hyper-resistance to cell wall perturbing agents, including congo red, calcofluor white and caffeine. Additionally, we noticed an increased phosphorylation of Mkc1 cell integrity MAP kinase upon AmB treatment. Collectively, these data identify differences in the transcriptional landscapes of AmB-resistant vs AmB-senstive isolates, and provide a framework for the mechanistic understanding of AmB resistance in C. auris.
2022-05-02 | GSE190920 | GEO
Project description:Aneuploidy and the evolution of aneuploid karyotypes of Candida albicans strains was identified using aCGH. Whole chromosome and segmental aneuploidies, (specifically on the left arm of chromosome 5 - shown to be due to isochromosome formation) are associated with the appearance of resistance to the antifungal drug fluconazole. Keywords: Comparative Genomic Hybridization
2006-06-30 | GSE4995 | GEO
Project description:Candida auris is an emerging fungal pathogen known for its high resistance to fluconazole, the most commonly prescribed antifungal. However, the genetic regulators of fluconazole susceptibility remain insufficiently understood in C. auris. Using a pooled screen of piggyBac (PB) transposition mutants, we identify significant enrichment of mitochondrial genes whose inactivation causes reduced fluconazole susceptibility. Genome-wide genetic interaction analysis of a representative mitochondrial gene-deleted mutant, pet309Δ, implicates that mitochondrial dysfunction reduces fluconazole susceptibility by enhancing Cdr1 efflux activity post-transcriptionally and through the vacuolar calcium pump homolog Cdt1. We further demonstrate that Cdt1, beyond its canonical calcium-pumping function, mediates fluconazole efflux, evidenced by its fluconazole-induced, calcineurin-dependent plasma membrane localization and dependence on ATP hydrolysis. Additionally, Cdt1 accelerates the evolution of fluconazole resistance, and its transcript levels correlate with susceptibility across clinical isolates. Our findings define a novel role for Cdt1 in fluconazole efflux in C. auris.
2026-01-06 | GSE300783 | GEO
Project description:The emergence of Candida auris poses a significant health challenge that has led to a new era of multidrug-resistant fungal infections. Invasive infections caused by C. auris are usually associated with remarkable morbidity and mortality. For many years, amphotericin B (AmB) remained the most efficient and the last line of treatment against most hard-to-treat fungal infections. However, strains of C. auris possess extraordinary resistance to most antifungal agents, including AmB. In this study, we screened ~2600 FDA-approved drugs and clinical compounds to identify the antiemetic drug rolapitant as a promising enhancer to AmB against C. auris. Rolapitant exhibited potent synergistic interactions with AmB against all tested (29/29) C. auris isolates. In a time-kill assay, rolapitant restored the fungicidal activity of AmB within 4 h. Additionally, the synergistic relationship between rolapitant and AmB was observed against other medically crucial Candida, Cryptococcus and Aspergillus species with ΣFICI that ranged from 0.16 to 0.5. In a transcriptomic study, ion transporters and ATP generation were identified as primary pathways impacted in C. auris AR0390 cells exposed to rolapitant. An ATP luminescence assay confirmed that rolapitant, at sub-inhibitory concentrations, significantly interfered with ATP production in C. auris. Moreover, rolapitant enhanced the in vivo activity of AmB in a mouse model of disseminated C. auris infection, as the combination reduced the fungal burden in murine kidneys by ~1 log (~90%) colony forming units. Our findings warrant further investigation of using rolapitant to overcome AmB resistance in C. auris and other fungal species.
2024-09-26 | GSE263806 | GEO
Project description:Candida auris (Candidozyma auris) is a yeast pathogen that poses a public health threat because of its ability to develop antifungal resistance. Notably, most C. auris isolates are resistant to fluconazole. The efflux pump Cdr1 is a key contributor of azole resistance in C. auris. In C. albicans, Cdr1 is regulated by the transcription factor Tac1, which has two orthologs in C. auris (Tac1a and Tac1b). While the role of Tac1b has been described, little is known about Tac1a. In this study, we characterized the respective roles of Tac1a and Tac1b in azole resistance. To investigate their transcriptional regulation and binding targets, we performed RNA sequencing and ChEC-seq (Chromatin endogenous cleavage sequencing) for both transcription factors. RNA sequencing was carried out by comparing hyperactivated mutants (TAC1a-HA or TAC1b-HA) with the wild-type strain IV.1. ChEC-seq was performed in strains carrying endogenous C-terminal MNase fusions (TAC1a-MNase and TAC1b-MNase) and in a control strain expressing ectopically MNase (Free MNase). Both Tac1a and Tac1b mediate azole resistance in C. auris via regulation of Cdr1, with overlapping downstream targets and evidence of autoregulation.
2025-09-13 | GSE307436 | GEO