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Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance
Sang Hu Kim1; Kali R. Iyer1; Lakhansing Pardeshi2; José F. Muñoz3; Nicole Robbins1; Christina A. Cuomo3; Koon Ho Wong4,5; Leah E. Cowen1
2019
Source PublicationMBIO
ISSN2150-7511
Volume10Issue:1
Abstract

Candida auris is an emerging fungal pathogen and a serious global health threat as the majority of clinical isolates display elevated resistance to currently available antifungal drugs. Despite the increased prevalence of C. auris infections, the mechanisms governing drug resistance remain largely elusive. In diverse fungi, the evolution of drug resistance is enabled by the essential molecular chaperone Hsp90, which stabilizes key regulators of cellular responses to drug-induced stress. Hsp90 also orchestrates temperature-dependent morphogenesis in Candida albicans, a key virulence trait. However, the role of Hsp90 in the pathobiology of C. auris remains unknown. In order to study regulatory functions of Hsp90 in C. auris, we placed HSP90 under the control of a doxycycline-repressible promoter to enable transcriptional repression. We found that Hsp90 is essential for growth in C. auris and that it enables tolerance of clinical isolates with respect to the azoles, which inhibit biosynthesis of the membrane sterol ergosterol. High-level azole resistance was independent of Hsp90 but dependent on the ABC transporter CDR1, deletion of which resulted in abrogated resistance. Strikingly, we discovered that C. auris undergoes a morphogenetic transition from yeast to filamentous growth in response to HSP90 depletion or cell cycle arrest but not in response to other cues that induce C. albicans filamentation. Finally, we observed that this developmental transition is associated with global transcriptional changes, including the induction of cell wall-related genes. Overall, this report provides a novel insight into mechanisms of drug tolerance and resistance in C. auris and describes a developmental transition in response to perturbation of a core regulator of protein homeostasis.

IMPORTANCE Fungal pathogens pose a serious threat to public health. Candida auris is an emerging fungal pathogen that is often resistant to commonly used antifungal drugs. However, the mechanisms governing drug resistance and virulence in this organism remain largely unexplored. In this study, we adapted a conditional expression system to modulate the transcription of an essential gene, HSP90, which regulates antifungal resistance and virulence in diverse fungal pathogens. We showed that Hsp90 is essential for growth in C. auris and is important for tolerance of the clinically important azole antifungals, which block ergosterol biosynthesis. Further, we established that the Cdr1 efflux transporter regulates azole resistance. Finally, we discovered that C. auris transitions from yeast to filamentous growth in response to Hsp90 inhibition, accompanied by global transcriptional remodeling. Overall, this work provides a novel insight into mechanisms regulating azole resistance in C. auris and uncovers a distinct developmental program regulated by Hsp90.

KeywordAntifungal Drug Resistance Candida Albicans Candida Auris Cdr1 Developmental Program Emerging Pathogen Fungal Morphogenesis Fungal Pathogen Hsp90 Transcriptional Program
DOI10.1128/mBio.02529-18
Indexed BySCIE
Language英语
WOS Research AreaMicrobiology
WOS SubjectMicrobiology
WOS IDWOS:000460314300050
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Cited Times [WOS]:13   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorLeah E. Cowen
Affiliation1.Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
2.Genomics and Bioinformatics Core, Faculty of Health Sciences, University of Macau, Macau, China
3.Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
4.Faculty of Health Sciences, University of Macau, Macau, China
5.Institute of Translational Medicine, University of Macau, Macau, China
Recommended Citation
GB/T 7714
Sang Hu Kim,Kali R. Iyer,Lakhansing Pardeshi,et al. Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance[J]. MBIO,2019,10(1).
APA Sang Hu Kim.,Kali R. Iyer.,Lakhansing Pardeshi.,José F. Muñoz.,Nicole Robbins.,...&Leah E. Cowen.(2019).Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance.MBIO,10(1).
MLA Sang Hu Kim,et al."Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance".MBIO 10.1(2019).
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