Experimental evolution identifies adaptive aneuploidy as a mechanism of fluconazole resistance in Candida auris
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ABSTRACT:
ORGANISM(S): Candidozyma auris
PROVIDER: GSE136768 | GEO | 2019/09/04
REPOSITORIES: GEO
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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
Project description:Experimental evolution identifies adaptive aneuploidy as a mechanism of fluconazole resistance in Candida auris
| PRJNA563631 | ENA
Project description:In this study, we designed a novel antifungal agent, PQA-Az-13 that demonstrated antifungal activity against C. auris biofilms. Cellular proteomics indicated that PQA-Az-13 partially or completely inhibited numerous enzymatic proteins in C. auris biofilms, particularly those involved in both amino acid biosynthesis and metabolism processes, as well as in general energy-producing processes. Due to its hydrophobic nature and limited aqueous solubility, PQA-Az-13 was encapsulated in cationic liposomes and characterized by biophysical and spectral techniques. PQA-Az-13 liposomes demonstrated enhanced antifungal activity levels against both C. auris in in vitro biofilms and ex vivo skin colonization models.
2023-12-07 | PXD046911 | Pride
Project description:Transcriptomic analysis of different Candida auris clinical isolates with distinct antifungal susceptibility profiles.
2021-01-30 | GSE165762 | GEO
Project description:Candida auris has become a serious threat to public health. The mechanisms of how this fungal pathogen adapts to the mammalian host are poorly understood. Here we report the rapid evolution of an adaptive C. auris multicellular aggregative morphology in the murine host during systemic infection. C. auris aggregative cells accumulate in the brain and exhibit obvious advantages over the single-celled yeast-form cells during systemic infection. Genetic mutations, specifically de novo point mutations in genes associated with cell division or budding processes, underlie the rapid evolution of this aggregative phenotype. Most mutated C. auris genes are associated with the regulation of cell wall integrity, cytokinesis, cytoskeletal properties, and cellular polarization. Moreover, the multicellular aggregates are notably more recalcitrant to the host antimicrobial peptides LL-37 and PACAP relative to the single-celled yeast-form cells. Overall, to survive in the host, C. auris can rapidly evolve a multicellular aggregative morphology via genetic mutations.
| S-EPMC10944540 | biostudies-literature
Project description:Background and purposeCandida auris, as a new characterized pathogenic yeast, has attracted remarkable attention in the recent decade due to its rapid global emergence and multidrug resistance traits. This unique species is able to cause nosocomial outbreaks and tolerate adverse conditions; however, it has been mostly misidentified by conventional methods.Case reportThis report aimed to describe the first fluconazole-resistant case of C. auris otitis in an immunocompetent patient in Iran. The isolate showed minimum inhibitory concentration of ≥ 32 μg/ml for fluconazole; however, the patient was treated with topical clotrimazole and miconazole with no recurrence.ConclusionThis was the second strain of C. auris isolated from otitis in Iran which was fluconazole-resistant, unlike the first Iranian isolate.
| S-EPMC8443880 | biostudies-literature
Project description:Myriocin exhibited very low MIC values (0.016 to 0.4 mg/L) to all C. auris isolates including several multidrug-resistant strains. The yeast-form, filamentous, or aggregating-form cells were all susceptible to the chemical. The antifungal effect was majorly due to the fungistatic activity, although an extended treatment could lead to the fungicidal activity to C. auris cells. Transcriptomic analysis demonstrates that myriocin suppresses the cellular metabolic activity and induces the expression of stress or antifungal response genes.
2020-12-03 | GSE161599 | GEO
Project description:Candida albicans is a prevalent, opportunistic, human fungal pathogen. Antifungal drug resistance and tolerance are two distinct mechanisms of adaptation to drugs. Studies of mechanisms of drug resistance are limited to the applications of high doses of drugs. Few studies have investigated the effects of subinhibitory amounts of drugs on the development of drug resistance or tolerance. In this study, we found that growth in a subinhibitory amount of fluconazole (FLC), a widely used antifungal drug, for just a short time was sufficient to induce aneuploidy in C. albicans. Surprisingly, the aneuploids displayed fitness loss in the presence of subinhibitory FLC, but a subpopulation of cells could tolerate up to 128 μg/mL FLC. Particular aneuploidy (ChrR trisomy) caused tolerance, not resistance, to FLC. In the absence of FLC, the aneuploids were unstable. Depending on the karyotype, aneuploids might become completely euploid or maintain particular aneuploidy, and, accordingly, the tolerance would be lost or maintained. Mechanistically, subinhibitory FLC was sufficient to induce the expression of several ERG genes and as well as the drug efflux gene MDR1. Aneuploids had a constitutive high-level expression of genes on and outside the aneuploid chromosomes, including most of the ERG genes as well as the drug efflux genes MDR1 and CDR2. Therefore, aneuploids were prepared for FLC challenges. In summary, aneuploidy provides a rapid and reversible strategy of adaptation when C. albicans is challenged with subinhibitory concentrations of FLC. IMPORTANCE Genome instability is a hallmark of C. albicans. Aneuploidy usually causes fitness loss in the absence of stress but confers better fitness under particular stress conditions. Therefore, aneuploidy is considered to be a double-edged sword. Here, we extend the understanding of aneuploidy. We found that aneuploidy arose under weak stress conditions but that it did not confer better fitness to the stress. Instead, it was less fit than its euploid counterparts. If the stress was withdrawn, aneuploidy spontaneously reverted to euploidy. If the stress became stronger, aneuploidy enabled subpopulation growth in a dose-independent manner of the stress. Therefore, we posit that aneuploidy enables the rapid and reversible development of drug tolerance in C. albicans. Further studies are required to investigate whether this is a general mechanism in human fungal pathogens.
| S-EPMC10101127 | biostudies-literature
Project description:The recently emerged pathogenic yeast Candida auris is a major concern for human health, because it is easily transmissible, difficult to eradicate from hospitals, and highly drug resistant. Most C. auris isolates are resistant to the widely used antifungal drug fluconazole due to mutations in the target enzyme Erg11 and high activity of efflux pumps, such as Cdr1. In the well-studied, distantly related yeast Candida albicans, overexpression of drug efflux pumps also is a major mechanism of acquired fluconazole resistance and caused by gain-of-function mutations in the zinc cluster transcription factors Mrr1 and Tac1. In this study, we investigated a possible involvement of related transcription factors in efflux pump expression and fluconazole resistance of C. auris The C. auris genome contains three genes encoding Mrr1 homologs and two genes encoding Tac1 homologs, and we generated deletion mutants lacking these genes in two fluconazole-resistant strains from clade III and clade IV. Deletion of TAC1b decreased the resistance to fluconazole and voriconazole in both strain backgrounds, demonstrating that the encoded transcription factor contributes to azole resistance in C. auris strains from different clades. CDR1 expression was not or only minimally affected in the mutants, indicating that Tac1b can confer increased azole resistance by a CDR1-independent mechanism.IMPORTANCE Candida auris is a recently emerged pathogenic yeast that within a few years after its initial description has spread all over the globe. C. auris is a major concern for human health, because it can cause life-threatening systemic infections, is easily transmissible, and is difficult to eradicate from hospital environments. Furthermore, C. auris is highly drug resistant, especially against the widely used antifungal drug fluconazole. Mutations in the drug target and high activity of efflux pumps are associated with azole resistance, but it is not known how drug resistance genes are regulated in C. auris We have investigated the potential role of several candidate transcriptional regulators in the intrinsic fluconazole resistance of C. auris and identified a transcription factor that contributes to the high resistance to fluconazole and voriconazole of two C. auris strains from different genetic clades, thereby providing insight into the molecular basis of drug resistance of this medically important yeast.
| S-EPMC7178551 | biostudies-literature
Project description:Candida auris has emerged as a multidrug-resistant pathogen of great clinical concern. Approximately 90% of clinical C. auris isolates are resistant to fluconazole, the most commonly prescribed antifungal agent, and yet it remains unknown what mechanisms underpin this fluconazole resistance. To identify novel mechanisms contributing to fluconazole resistance in C. auris, fluconazole-susceptible C. auris clinical isolate AR0387 was passaged in media supplemented with fluconazole to generate derivative strains which had acquired increased fluconazole resistance in vitro Comparative analyses of comprehensive sterol profiles, [3H]fluconazole uptake, sequencing of C. auris genes homologous to genes known to contribute to fluconazole resistance in other species of Candida, and relative expression levels of C. aurisERG11, CDR1, and MDR1 were performed. All fluconazole-evolved derivative strains were found to have acquired mutations in the zinc-cluster transcription factor-encoding gene TAC1B and to show a corresponding increase in CDR1 expression relative to the parental clinical isolate, AR0387. Mutations in TAC1B were also identified in a set of 304 globally distributed C. auris clinical isolates representing each of the four major clades. Introduction of the most common mutation found among fluconazole-resistant clinical isolates of C. auris into fluconazole-susceptible isolate AR0387 was confirmed to increase fluconazole resistance by 8-fold, and the correction of the same mutation in a fluconazole-resistant isolate, AR0390, decreased fluconazole MIC by 16-fold. Taken together, these data demonstrate that C. auris can rapidly acquire resistance to fluconazole in vitro and that mutations in TAC1B significantly contribute to clinical fluconazole resistance.IMPORTANCECandida auris is an emerging multidrug-resistant pathogen of global concern, known to be responsible for outbreaks on six continents and to be commonly resistant to antifungals. While the vast majority of clinical C. auris isolates are highly resistant to fluconazole, an essential part of the available antifungal arsenal, very little is known about the mechanisms contributing to resistance. In this work, we show that mutations in the transcription factor TAC1B significantly contribute to clinical fluconazole resistance. These studies demonstrated that mutations in TAC1B can arise rapidly in vitro upon exposure to fluconazole and that a multitude of resistance-associated TAC1B mutations are present among the majority of fluconazole-resistant C. auris isolates from a global collection and appear specific to a subset of lineages or clades. Thus, identification of this novel genetic determinant of resistance significantly adds to the understanding of clinical antifungal resistance in C. auris.
| S-EPMC7218281 | biostudies-literature