Overcoming amphotericin B resistance in Candida auris using the antiemetic drug, rolapitant
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ABSTRACT:
PROVIDER: PRJNA1099273 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28637102_1.fastq.gz | Fastqsanger.gz | |||
| SRR28637102_2.fastq.gz | Fastqsanger.gz | |||
| SRR28637103_1.fastq.gz | Fastqsanger.gz | |||
| SRR28637103_2.fastq.gz | Fastqsanger.gz | |||
| SRR28637104_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
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 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: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:Comparative transcriptomic profiling of Candida auris RCA1 and EFG1 null mutants in comparison to the Wild-Type Strain
2025-05-30 | GSE253332 | GEO
Project description:Candida auris reference strain B11221 was exposed to sub-inhibitory (1μg/ml) and inhibitory (8μg/ml) tunicamycin for 3h. Transcriptomes were compared to no drug treatment control.
2023-12-23 | E-MTAB-12667 | biostudies-arrayexpress
Project description:The expression difference for haploid and deploid of Candida auris
2020-09-13 | GSE149284 | GEO
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:Invasive fungal infections are important healthcare associated disease worldwide especially in intensive care units More recently, Candida auris a multidrug and potentially pan-resistant species has globally emerged as a new nosocomial pathogen, which has been already reported from at least 50 countries on six continents. Clinical studies showed that previously well-defined phylogenetic C. auris clades display significant differences regarding their pathogenicity, virulence, metabolism and susceptibility profile to traditional antifungal therapies. Based on epidemiological data, isolates belonging to the South Asian clade show the highest ratio of resistance to fluconazole (97%), amphotericin B (47%) and this clade involves the highest number of multidrug resistant isolates (45%), which compromise the efficacy of applied antifungal therapy. In the past decade, a new broad-spectrum antifungal drug, isavuconazole (ISA), has been introduced into clinical practice. ISA is primarily approved for the treatment of invasive aspergillosis and mucormycosis, and currently, there are no available recommendations for the therapy of invasive Candida infections. In our previous study, we reported different ISA susceptibility profiles between isolates belonging to South Asian lineage. However, the global transcriptional - even isolate specific - response remained unresolved. Therefore, our study aimed to reveal those molecular events, which are associated with ISA exposure using high throughput RNA sequencing (RNAseq).
2024-08-24 | GSE275177 | GEO
Project description:Comparative Transcriptomics Reveal Determinants of Amphotericin B Resistance in Candida auris
| PRJNA788930 | ENA