Limited
            <i>ERG11</i>
            Mutations Identified in Isolates of Candida auris Directly Contribute to Reduced Azole Susceptibility

Healey, Kelley R.; Kordalewska, Milena; Ortigosa, Cristina Jiménez; Singh, Ashutosh; Berrío, Indira; Chowdhary, Anuradha; Perlin, David S.

doi:10.1128/aac.01427-18

Cited by 151 publications

(153 citation statements)

References 23 publications

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“…Recently, sequence divergences/mutations on ERG11 in C. auris have been shown to be associated with resistance to azoles (47). However, the ERG11 mutations by themselves cannot explain why the level of fluconazole resistance was lower (up to 128 µg/mL) when the C. auris gene was expressed in S. cerevisiae (48). Therefore, our data combined with reports from the literature suggest that the fluconazole resistance in C. auris is due to modifications of multiple steps in the ergosterol biosynthesis pathway.…”

Section: Discussionmentioning

confidence: 99%

Candida auris: multi-omics signature of an emerging and multidrug-resistant pathogen

Zamith-Miranda

Heyman

Cleare

et al. 2019

Preprint

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Candida auris is a recently described pathogenic fungus that is causing invasive 24 outbreaks on all continents. The fungus is of high concern given the numbers of multidrug-25 resistant strains that have been isolated in distinct sites across the globe. The fact that its 26 diagnosis is still problematic suggests that the spreading of the pathogen remains 27 underestimated. Notably, the molecular mechanisms of virulence and antifungal resistance 28 employed by this new species are largely unknown. In the present work, we compared two 29 clinical isolates of C. auris with distinct drug susceptibility profiles and a Candida albicans 30 reference strain using a multi-omics approach. Our results show that, despite the distinct 31 drug-resistance profile, both C. auris strains appear to be very similar, albeit with a few 32 notable differences. However, when compared to C. albicans both C. auris strains have 33 major differences regarding their carbon utilization and downstream lipid and protein 34 content, suggesting a multi-factorial mechanism of drug resistance. The molecular profile 35 displayed by C. auris helps to explain the antifungal resistance and virulence phenotypes of 36 this new emerging pathogen. 37Importance: Candida auris was firstly described in Japan in 2009 and has now been the 38 cause of significant outbreaks across the globe. The high number of isolates that are 39 resistant to one or more antifungals, as well as the high mortality rates from patients with 40 bloodstream infections, has caught the attention of the medical mycology, infectious 41 disease and public health communities to this pathogenic fungus. In the current work, we 42 performed a broad multi-omics approach on two clinical isolates isolated in New York, the 43 most affected area in the USA and found that the omic profile of C. auris differs 44 3 significantly from C. albicans. Besides our insights into C. auris carbon utilization and 45 lipid and protein content, we believe that the availability of these data will enhance our 46 ability to combat this rapidly emerging pathogenic yeast. 48Candida auris is an emerging pathogenic fungus that was firstly described in 2009 after 49 being isolated from the ear discharge of a patient in Tokyo, Japan (1). After the new species 50 identification, a study in South Korea reported a misidentified C. auris strain isolated in 51 1996, which then became the first known case of human C. auris infection (2). Despite the 52 fact that bloodstream infections are the main cause of mortality among Candida spp 53 infections, C. auris strains have been isolated from various sites such as respiratory tract, 54 bones, and central nervous system (3) as well as on a variety of abiotic surfaces (4), which 55 suggests a metabolic plasticity to survive in distinct environments. The reports of C. auris 56 outbreaks in all continents suggest that this pathogen is spreading rapidly across the globe 57 and many of the isolated strains are resistant to at least one class of antifungals, or even 58 multidrug-re...

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Section: Discussionmentioning

confidence: 99%

Candida auris: multi-omics signature of an emerging and multidrug-resistant pathogen

Zamith-Miranda

Heyman

Cleare

et al. 2019

Preprint

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“…Studies on susceptibility to antifungal agents revealed that resistance to azole compounds is predominantly caused by the acquisition of various universal and species-specific mutations in the genes encoding lanosterol-alpha demethylase (ERG11) in yeast species [139][140][141] and cytochrome P-51A (cyp5A1) in A. fumigatus [142]. Overexpression of efflux pumps and azole target genes is also a contributing factor.…”

Section: Rapid Identification Of Antifungal Resistance Using Moleculamentioning

confidence: 99%

Identification of Mycoses in Developing Countries

Arastehfar

Wickes

İlkit

et al. 2019

JoF

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Extensive advances in technology offer a vast variety of diagnostic methods that save time and costs, but identification of fungal species causing human infections remains challenging in developing countries. Since the echinocandins, antifungals widely used to treat invasive mycoses, are still unavailable in developing countries where a considerable number of problematic fungal species are present, rapid and reliable identification is of paramount importance. Unaffordability, large footprints, lack of skilled personnel, and high costs associated with maintenance and infrastructure are the main factors precluding the establishment of high-precision technologies that can replace inexpensive yet time-consuming and inaccurate phenotypic methods. In addition, point-of-care lateral flow assay tests are available for the diagnosis of Aspergillus and Cryptococcus and are highly relevant for developing countries. An Aspergillus galactomannan lateral flow assay is also now available. Real-time PCR remains difficult to standardize and is not widespread in countries with limited resources. Isothermal and conventional PCR-based amplification assays may be alternative solutions. The combination of real-time PCR and serological assays can significantly increase diagnostic efficiency. However, this approach is too expensive for medical institutions in developing countries. Further advances in next-generation sequencing and other innovative technologies such as clustered regularly interspaced short palindromic repeats (CRISPR)-based diagnostic tools may lead to efficient, alternate methods that can be used in point-of-care assays, which may supplement or replace some of the current technologies and improve the diagnostics of fungal infections in developing countries.

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“…Most of these fluconazole-resistant clinical isolates of C. auris have been found to harbor mutations in the gene encoding the sterol demethylase enzyme inhibited by the triazoles, ERG11, and the most commonly identified mutations (encoding F126L, Y132F, and K143R) have been demonstrated to contribute to triazole resistance in other species of Candida. Furthermore, when C. auris ERG11 alleles harboring mutations encoding the Y132F or K143R amino acid substitution were episomally expressed in Saccharomyces cerevisiae, fluconazole MICs were observed to increase (8). However, fluconazole-susceptible isolates of C. auris (fluconazole MIC, 1 to 8 mg/liter) harboring the Y132F or K143R mutation have been reported, suggesting the presence of additional mechanisms of triazole resistance yet to be identified (1,9).…”

mentioning

confidence: 99%

Abrogation of Triazole Resistance upon Deletion of CDR1 in a Clinical Isolate of Candida auris

Rybak

Doorley

Nishimoto

et al. 2019

Antimicrob Agents Chemother

111

140

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Candida auris has rapidly emerged as a health care-associated and multidrug-resistant pathogen of global concern. In this work, we examined the relative expression of the four C. auris genes with the highest degree of homology to Candida albicans CDR1 and MDR1 among three triazole-resistant clinical isolates as compared to the triazole-susceptible genome reference clinical isolate. We subsequently utilized a novel Cas9-mediated system for genetic manipulations to delete C. auris CDR1 and MDR1 in both a triazole-resistant clinical isolate and a susceptible reference strain and observed that MICs for all clinically available triazoles decreased as much as 128-fold in the CDR1 deletion strains. The findings of this work reveal for the first time that C. auris CDR1 and MDR1 are more highly expressed among triazole-resistant clinical isolates of C. auris and that the overexpression of CDR1 is a significant contributor to clinical triazole resistance.

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Limited ERG11 Mutations Identified in Isolates of Candida auris Directly Contribute to Reduced Azole Susceptibility

Cited by 151 publications

References 23 publications

Candida auris: multi-omics signature of an emerging and multidrug-resistant pathogen

Candida auris: multi-omics signature of an emerging and multidrug-resistant pathogen

Identification of Mycoses in Developing Countries

Abrogation of Triazole Resistance upon Deletion of CDR1 in a Clinical Isolate of Candida auris

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