Acquired amphotericin B resistance attributed to a mutated ERG3 in Candidozyma auris

Massic, Lauryn; Doorley, Laura A.; Jones, Sarah J.; Richardson, Irene; Siao, Danielle Denise; Siao, Lauren; Dykema, Philip; Hua, Chi; Schneider, Emily; Cuomo, Christina A.; Rogers, P. David; Hooser, Stephanie Van; Parker, Josie E.; Kelly, Steven; Hess, David; Rybak, Jeffrey M.; Pandori, Mark

doi:10.1128/aac.00601-25

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Acquired amphotericin B resistance attributed to a mutated ERG3 in Candidozyma auris

Lauryn Massic

, Laura A. Doorley

, Sarah J. Jones, Irene Richardson, Danielle Denise Siao, Lauren Siao, Philip Dykema

, Chi Hua, Emily Schneider, Christina A. Cuomo, P. David Rogers

, Stephanie Van Hooser, Josie E. Parker

, Steven Kelly, David Hess, Jeffrey M. Rybak

, Mark Pandori

Antimicrobial Agents and Chemotherapy, Start page: e00601-25

Swansea University Author: Steven Kelly

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DOI (Published version): 10.1128/aac.00601-25

Abstract

First identified in 2009, Candidozyma auris (formerly Candida auris) is an emerging multidrug-resistant fungus that can cause invasive infections with a crude mortality rate ranging from 30 to 60%. Currently, 30–50% of C. auris isolates are intrinsically resistant to amphotericin B. In this study, w...

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Published in:	Antimicrobial Agents and Chemotherapy
ISSN:	0066-4804 1098-6596
Published:	American Society for Microbiology 2025
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa70522

first_indexed	2025-09-26T15:06:28Z
last_indexed	2025-10-31T18:12:33Z
id	cronfa70522
recordtype	SURis
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spelling	2025-10-30T14:34:14.6547168 v2 70522 2025-09-26 Acquired amphotericin B resistance attributed to a mutated ERG3 in Candidozyma auris b17cebaf09b4d737b9378a3581e3de93 Steven Kelly Steven Kelly true false 2025-09-26 First identified in 2009, Candidozyma auris (formerly Candida auris) is an emerging multidrug-resistant fungus that can cause invasive infections with a crude mortality rate ranging from 30 to 60%. Currently, 30–50% of C. auris isolates are intrinsically resistant to amphotericin B. In this study, we characterized a clinical case of acquired amphotericin B resistance using whole-genome sequencing, a large-scale phenotypic screen, comprehensive sterol profiling, and genotypic reversion using CRISPR. Data obtained in this study provide evidence that a deletion resulting in a frameshift in ERG3 significantly contributes to the observed resistant phenotype, and a nonsense mutation in ERG4 may more modestly contribute to resistance. Characterization of this isolate also revealed that a fitness cost is associated with the abrogation of ergosterol production and its replacement with other late-stage sterols. This article presents a clinical case description of amphotericin B resistance from a frameshift mutation in ERG3 in C. auris and marks an advancement in the understanding of antifungal resistance in this fungal pathogen. Journal Article Antimicrobial Agents and Chemotherapy 0 e00601-25 American Society for Microbiology 0066-4804 1098-6596 microbial, public health, genetics, ERG3, amphotericin B, multidrug resistance, Candida auris 22 9 2025 2025-09-22 10.1128/aac.00601-25 COLLEGE NANME COLLEGE CODE Swansea University Another institution paid the OA fee This research was supported in part by the ALSAC and the National Cancer Institute grant P30 CA021765, NIH NIAID grant R01 AI169066 awarded to P.D.R. and C.A.C, NIAID grant U19AI110818 to the Broad Institute (C.A.C.), the St. Jude Children’s Research Hospital Children’s Infection Defense Center grant (J.M.R.), and the Society of Infectious Diseases Pharmacists Young Investigator Research Award granted to J.M.R. This publication was supported by the Nevada State Department of Health and Human Services through Grant # 5 NU50CK000560-05-00 from Epidemiology and Laboratory Capacity for Infectious Diseases (ELC), its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Department nor Epidemiology and Laboratory Capacity for Infectious Diseases (ELC). 2025-10-30T14:34:14.6547168 2025-09-26T15:56:35.8987203 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Lauryn Massic 0009-0006-7245-3182 1 Laura A. Doorley 0000-0002-1695-9561 2 Sarah J. Jones 3 Irene Richardson 4 Danielle Denise Siao 5 Lauren Siao 6 Philip Dykema 0000-0002-2158-3175 7 Chi Hua 8 Emily Schneider 9 Christina A. Cuomo 10 P. David Rogers 0000-0002-4401-0679 11 Stephanie Van Hooser 12 Josie E. Parker 0000-0002-3855-4194 13 Steven Kelly 14 David Hess 15 Jeffrey M. Rybak 0000-0002-9317-0935 16 Mark Pandori 0000-0003-0334-1946 17 70522__35490__e299152152d84136955856d4366c7107.pdf 70522.VOR.pdf 2025-10-28T15:45:36.4385596 Output 698123 application/pdf Version of Record true Copyright © 2025 Massic et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. true eng https://creativecommons.org/licenses/by/4.0/
title	Acquired amphotericin B resistance attributed to a mutated ERG3 in Candidozyma auris
spellingShingle	Acquired amphotericin B resistance attributed to a mutated ERG3 in Candidozyma auris Steven Kelly
title_short	Acquired amphotericin B resistance attributed to a mutated ERG3 in Candidozyma auris
title_full	Acquired amphotericin B resistance attributed to a mutated ERG3 in Candidozyma auris
title_fullStr	Acquired amphotericin B resistance attributed to a mutated ERG3 in Candidozyma auris
title_full_unstemmed	Acquired amphotericin B resistance attributed to a mutated ERG3 in Candidozyma auris
title_sort	Acquired amphotericin B resistance attributed to a mutated ERG3 in Candidozyma auris
author_id_str_mv	b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv	b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author	Steven Kelly
author2	Lauryn Massic Laura A. Doorley Sarah J. Jones Irene Richardson Danielle Denise Siao Lauren Siao Philip Dykema Chi Hua Emily Schneider Christina A. Cuomo P. David Rogers Stephanie Van Hooser Josie E. Parker Steven Kelly David Hess Jeffrey M. Rybak Mark Pandori
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institution	Swansea University
issn	0066-4804 1098-6596
doi_str_mv	10.1128/aac.00601-25
publisher	American Society for Microbiology
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
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hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description	First identified in 2009, Candidozyma auris (formerly Candida auris) is an emerging multidrug-resistant fungus that can cause invasive infections with a crude mortality rate ranging from 30 to 60%. Currently, 30–50% of C. auris isolates are intrinsically resistant to amphotericin B. In this study, we characterized a clinical case of acquired amphotericin B resistance using whole-genome sequencing, a large-scale phenotypic screen, comprehensive sterol profiling, and genotypic reversion using CRISPR. Data obtained in this study provide evidence that a deletion resulting in a frameshift in ERG3 significantly contributes to the observed resistant phenotype, and a nonsense mutation in ERG4 may more modestly contribute to resistance. Characterization of this isolate also revealed that a fitness cost is associated with the abrogation of ergosterol production and its replacement with other late-stage sterols. This article presents a clinical case description of amphotericin B resistance from a frameshift mutation in ERG3 in C. auris and marks an advancement in the understanding of antifungal resistance in this fungal pathogen.
published_date	2025-09-22T05:26:47Z
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Acquired amphotericin B resistance attributed to a mutated ERG3 in Candidozyma auris

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