Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1171956 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30963043_1.fastq.gz | Fastqsanger.gz | |||
| SRR30963043_2.fastq.gz | Fastqsanger.gz | |||
| SRR30963044_1.fastq.gz | Fastqsanger.gz | |||
| SRR30963044_2.fastq.gz | Fastqsanger.gz | |||
| SRR30963045_1.fastq.gz | Fastqsanger.gz |
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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.
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Project description:Comparative transcriptomic profiling of Candida auris RCA1 and EFG1 null mutants in comparison to the Wild-Type Strain
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Project description:Comparative transcriptomic profiling of Candida auris derivative clones collected from 5FC-containing medium in comparison to the Wild-Type Strain
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Project description:Candida auris is a recently found pathogenic yeast that causes systemic infections, showing a high mortality rate. The delay on making a correct diagnosis of C. auris is a current problem in the healthcare system setting. As immunoproteomics studies are important to identify immunoreactive proteins for new diagnostic strategies, in this study immunocompetent murine systemic infections caused by non-aggregative and aggregative phenotypes of C. auris, and by Candida albicans and Candida haemulonii were carried out, and the obtained sera were used to study their immunoreactivity against C. auris proteins. The aim was to identify the most immunoreactive antigens of this yeast. Thirteen spots were recognized by sera from mice infected with both C. auris phenotypes and analyzed by mass spectrometry. They corresponded to enolase, phosphoglycerate kinase, glyceraldehyde 3-phosphate dehydrogenase and phosphoglycerate mutase. These four proteins seem to be also recognized by sera obtained from human patients with disseminated C. auris infection, but not by sera obtained from mice infected with other fungi such as C. albicans or Aspergillus fumigatus. In conclusion, this study showed that the identified proteins could be potential candidates to be studied as new diagnostic or even therapeutic targets for C. auris.
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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.
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Project description:To mimic the initial phases of systemic Candida infections with dissemination via the bloodstream, we used an ex vivo whole blood infection model. Dual TP of C. auris in blood gave insights into fungal adaptations and survival mechanisms as well as the host response to the infection.
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Project description:This study aimed to characterise the transcriptional response of two strains of Candida auris (UACa11 and UACa20) during media-induced aggregation due to differences in phenotype. RNA was isolated from each strain under both aggregating and non-aggregating culture conditions.
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Project description:Candida auris wild type strain FY279 was used to tebuconazole adaptors. Transcriptomes of two adaptors, TJ42 and TJ44, were compared to wild type.
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Project description:Candida auris occupies similar niches in various infections as Pseudomonas aeruginosa; however, the details of their interspecies communication remain largely unknown. To gain deeper insights into this bacterial–fungal relationship, phenotypic and transcriptomic analyses were conducted in the presence of the primary P. aeruginosa quorum-sensing molecule, 3-oxo-C12-homoserine lactone (HSL), against C. auris, with the results compared to those of C. albicans. We demonstrated a significant HSL-induced reduction in adhesion of C. auris cells at 100- and 200-μM concentrations. Furthermore, HSL exposure reduced intracellular iron and zinc levels and modulated C. auris metabolism toward beta-oxidation, which may be associated with the observed reduction in in vivo virulence at lower HSL concentrations compared with C. albicans. RNA-sequencing transcriptome analysis revealed 67 and 306 upregulated genes, as well as 111 and 168 downregulated genes, in response to 100 and 200 μM HSL, respectively. We identified 45 overlapping upregulated and 25 overlapping downregulated genes between the two HSL concentrations. Our findings indicate that HSL-induced effects are not specific to C. albicans; additionally, several characteristics are present in C. auris but not in C. albicans following HSL exposure. Similar to other Candida-derived C12 compounds (e.g., farnesol), HSL reduces several C. auris survival strategies, which may significantly influence the nature of P. aeruginosa–C. auris co-habitation.
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