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Experimental evolution identifies adaptive aneuploidy as a mechanism of fluconazole resistance in Candida auris

ABSTRACT: Experimental evolution identifies adaptive aneuploidy as a mechanism of fluconazole resistance in Candida auris

PROVIDER: PRJNA563631 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10059687_1.fastq.gz	Fastqsanger.gz
	SRR10059687_2.fastq.gz	Fastqsanger.gz
	SRR10059688_1.fastq.gz	Fastqsanger.gz
	SRR10059688_2.fastq.gz	Fastqsanger.gz
	SRR10059689_1.fastq.gz	Fastqsanger.gz

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Experimental Evolution Identifies Adaptive Aneuploidy as a Mechanism of Fluconazole Resistance in Candida auris.

Project description:Candida auris is a newly emerging fungal pathogen of humans and has attracted considerable attention from both the clinical and basic research communities. Clinical isolates of C. auris are often resistant to one or more antifungal agents. To explore how antifungal resistance develops, we performed experimental evolution assays using a fluconazole-susceptible isolate of C. auris (BJCA001). After a series of passages through medium containing increasing concentrations of fluconazole, fungal cells acquired resistance. By sequencing and comparing the genomes of the parental fluconazole-susceptible strain and 26 experimentally evolved strains of C. auris, we found that a portion of fluconazole-resistant strains carried one extra copy of chromosome V. In the absence of fluconazole, C. auris cells rapidly became susceptible and lost the extra copy of chromosome V. Genomic and transcriptome sequencing (RNA-Seq) analyses indicate that this chromosome carries a number of drug resistance-related genes, which were transcriptionally upregulated in the resistant, aneuploid strains. Moreover, missense mutations were identified in the genes TAC1B, RRP6, and SFT2 in all experimentally evolved strains. Our findings suggest that the gain of an extra copy of chromosome V is associated with the rapid acquisition of fluconazole resistance and may represent an important evolutionary mechanism of antifungal resistance in C. auris.

| S-EPMC7927865 | biostudies-literature

Experimental evolution identifies adaptive aneuploidy as a mechanism of fluconazole resistance in Candida auris

Project description:In the current study, we set out to explore the developmental mechanism of antifungal resistance in this fungus using an in vitro experimental evolution strategy.

2019-09-04 | GSE136768 | GEO

The transcription factor Rpn4 activates its own and efflux pumps’ expression to confer fluconazole resistance in Candida auris

Project description:The goal of this RNA-Seq study is to elucidate Rpn4’s function in regulating C. auris fluconazole resistance.

2023-11-15 | GSE218140 | GEO

Whole genome sequencing of fluconazole (64 µg/ml) adaptors in Candida auris

Project description:Candida auris clade III isolate B12039 was spread on YPD plate supplemented with 64 µg/ml fluconazole. Randomly 45 adaptors were chosen for further analysis. We did sequencing of them as as well as the parent.

2021-06-21 | E-MTAB-10559 | biostudies-arrayexpress

Whole genome sequencing of fluconazole (128 µg/ml) adaptors in Candida auris

Project description:Candida auris clade III isolate B12039 was spread on YPD plate supplemented with 128 µg/ml fluconazole. Randomly 39 adaptors were chosen for further analysis. We did sequencing of them as as well as the parent.

2021-06-21 | E-MTAB-10560 | biostudies-arrayexpress

CGH analysis of Candida albicans strains after in vitro evolution in the presence or absence of Fluconazole

Project description:Here we provide, for the first time, a longitudinal study of the prevalence, dynamics, and fixation of gross chromosomal rearrangements, including aneuploidy, in the presence and absence of fluconazole during a well-controlled in vitro evolution experiment. While no aneuploidy was detected in any of the no-drug control populations, in all fluconazole-treated populations analyzed, isochromosome 5L [i(5L)] appeared soon after drug exposure, was associated with increased fitness in the presence of drug, and became fixed in independent populations. In two separate cases, larger supernumerary chromosomes composed of i(5L) attached to other chromosome fragments appeared and were later lost during exposure to the drug. Other aneuploidies, particularly trisomies of the smaller chromosomes (Chr3-7), appeared throughout the evolution experiment, and the rapid accumulation of multiple aneuploid chromosomes per cell coincided with the highest resistance to fluconazole.

2009-12-31 | GSE16423 | GEO

CGH analysis of Candida albicans strains after in vitro evolution in the presence or absence of Fluconazole

2010-06-24 | E-GEOD-16423 | biostudies-arrayexpress

Mechanisms of Adaptive Evolution of Aneuploid Cells

Project description:Alteration of normal ploidy (aneuploidy) is an important mechanism of evolution of species. It has been linked to a rapid response to stress and is regarded as a hallmark of cancer. While increased genomic instability of aneuploid cells can accelerate genetic diversification and facilitate adaptation, these cells also face the adverse effects of gene imbalance, resulting in fitness cost. Here, to understand the mechanisms through which cells respond to aneuploidy and develop tolerance leading to fitness restoration, we subjected disomic (i.e. with an extra chromosome copy) strains of yeast to long-term experimental evolution, forcing disomy maintenance with selection markers. We characterized mutations, karyotype alterations and gene expression changes throughout adaptive evolution, and analyzed them to dissect the associated molecular strategies. Cells with different extra chromosomes accumulated mutations at distinct rates, and endured a diverse array of adaptive events. Despite remarkable diversity of these events, cells tended to evolve towards normal ploidy through both chromosomal DNA loss and changes in gene expression. We identified genes commonly altered during the evolution of disomic strains, and genes recurrently mutated in multiple lines. Our analyses revealed protein translation, amino acid biosynthesis, transcription regulation, stress response, and nucleotide and protein degradation as key pathways for the adaptive response to aneuploidy and identified transcription factors that mediate this response. Together, these findings define cellular strategies that underlie tolerance to aneuploidy.

2018-08-31 | GSE119272 | GEO

Rapid in vitro evolution of flucytosine resistance in Candida auris

Project description:Comparative transcriptomic profiling of Candida auris derivative clones collected from 5FC-containing medium in comparison to the Wild-Type Strain

2024-08-22 | GSE272878 | GEO

Potent synergistic interactions between lopinavir and azole antifungal drugs against emerging multidrug-resistant Candida auris

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

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