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Comparative Transcriptomics Reveal Determinants of Amphotericin B Resistance in Candida auris

ABSTRACT: Comparative Transcriptomics Reveal Determinants of Amphotericin B Resistance in Candida auris

PROVIDER: PRJNA788930 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17259761_1.fastq.gz	Fastqsanger.gz
	SRR17259761_2.fastq.gz	Fastqsanger.gz
	SRR17259762_1.fastq.gz	Fastqsanger.gz
	SRR17259762_2.fastq.gz	Fastqsanger.gz
	SRR17259763_1.fastq.gz	Fastqsanger.gz

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Comparative Transcriptomics Reveal Determinants of Amphotericin B Resistance in Candida auris

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

Overcoming amphotericin B resistance in Candida auris using the antiemetic drug, rolapitant

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

Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris

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

Haploid and Deploid for Candida auris

Project description:The expression difference for haploid and deploid of Candida auris

2020-09-13 | GSE149284 | GEO

Transcriptional Signatures Predict Phenotypic Variations of Candida auris

Project description:Transcriptomic analysis of different Candida auris clinical isolates with distinct antifungal susceptibility profiles.

2021-01-30 | GSE165762 | GEO

Candida auris whole cell proteomics

Project description:Whole cell proteomics of Candida auris MMC1 and MMC2 strains.

2019-05-24 | PXD013456 | Pride

Candida auris extracellular vesicle proteomics

Project description:Proteomic analysis of extracellular vesicles from Candida auris MMC1 and MMC2 strains.

2021-11-12 | PXD026768 | Pride

Transcriptomics and phenotyping define signatures associated with echinocandin resistance in Candida auris

Project description:Transcriptomic analysis of different Candida auris clinical isolates

2022-03-16 | GSE198410 | GEO

Isolate specific transcriptome changes exerted by isavuconazole treatment in Candida auris

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

Overcoming amphotericin B resistance in Candida auris using the antiemetic drug, rolapitant

Project description:Overcoming amphotericin B resistance in Candida auris using the antiemetic drug, rolapitant

| PRJNA1099273 | ENA