In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris
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Abstract
Objective Candida auris has emerged as a health-care-associated and multidrug-resistant fungal pathogen of great clinical concern. As many as 50% of C. auris clinical isolates are reported to be resistant to amphotericin B, but no mechanisms contributing to this resistance have been identified. Here we describe a clinical case in which high-level amphotericin B resistance was acquired in vivo during therapy and undertake molecular and genetic studies to identify and characterize the genetic determinant of resistance.Methods Whole-genome sequencing was performed on four C. auris isolates obtained from a single patient case. Cas9-mediated genetic manipulations were then used to generate mutant strains harbouring mutations of interest, and these strains were subsequently subjected to amphotericin B susceptibility testing and comprehensive sterol profiling.Results A novel mutation in the C. auris sterol-methyltransferase gene ERG6 was found to be associated with amphotericin B resistance, and this mutation alone conferred a >32-fold increase in amphotericin B resistance. Comprehensive sterol profiling revealed an abrogation of ergosterol biosynthesis and a corresponding accumulation of cholesta-type sterols in isolates and strains harbouring the clinically derived ERG6 mutation.Conclusions Together these findings definitively demonstrate mutations in C. auris ERG6 as the first identified mechanism of clinical amphotericin B resistance in C. auris and represent a significant step forward in the understanding of antifungal resistance in this emerging public health threat.
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The ERG6 YY98V* truncation confers amphotericin B resistance but also causes a high fitness loss.
“For instance, the ERG6YY98V* truncation confers resistance but also causes a high fitness loss14.”
From Candida auris skin tropism and antifungal resistance are mediated by carbonic anhydrase Nce103 (2025) · cites this paper as [14]
The Results section ('Impact of ERG6 mutations on amphotericin B susceptibility'; page unavailable) reports that introducing ERG6YY98V* increased amphotericin B MIC by at least 32-fold. The Discussion (page unavailable) reports decreased growth rates in isolates and strains carrying the allele, but does not establish that the fitness loss was high or that the mutation itself caused it. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPrevious efforts focused on genetic variations cannot explain amphotericin B resistance in the majority of AMBR isolates, especially as AMBR has rarely been seen in other Candida pathogens.
“Although previous efforts focused on genetic variations10,14, they cannot explain this phenomenon in the majority of AMBR isolates, especially as AMBR has been rarely seen in other Candida pathogens.”
From Candida auris skin tropism and antifungal resistance are mediated by carbonic anhydrase Nce103 (2025) · cites this paper as [14]
The Introduction (page unavailable) says no mechanism of clinical amphotericin B resistance in C. auris had previously been identified, and the Discussion says an earlier analysis of 92 isolates, including 22 resistant isolates, did not associate ERG6 mutations with resistance. This supports the point that earlier genetic work had not explained resistance, but the paper does not establish that genetic variations cannot explain it in the majority of resistant isolates. The Discussion compares resistance levels in C. auris and C. glabrata; it does not say resistance is rare in other Candida pathogens. (LLM, conf=0.83)
Experimental — accuracy not yet measuredRare mutations in the ergosterol pathway gained during treatment promote amphotericin B resistance.
“Rare mutations in the ergosterol pathway10,14 gained during treatment promote AMBR.”
From Candida auris skin tropism and antifungal resistance are mediated by carbonic anhydrase Nce103 (2025) · cites this paper as [14]
In Candida species, amphotericin B resistance has been associated with mutations in several ergosterol biosynthesis genes, including ERG2, ERG3, ERG6, and ERG11.
“In Candida species, amphotericin B resistance has been associated with mutations in several ergosterol biosynthesis genes, including ERG2, ERG3, ERG6, and ERG1142,45–47.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [47]
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References 21 · Cited by 120
Research works printed but not linked: 1
- [16]Lombardi L, Oliveira-Pacheco J, Butler G, Plasmid-Based CRISPR-Cas9 Gene Editing in Multiple Candida Species. mSphere 2020; 5. PMC6416365 30867327
- Authors
- Rybak, J. M., Barker, K. S., Muñoz, J. F., Parker, J. E., Ahmad, S., Mokaddas, E., Abdullah, A., Elhagracy, R. S., Kelly, S. L., Cuomo, C. A., & Rogers, P. D.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Broad Institute (US)
- Swansea University (GB)
- Kuwait University (KW)
- Ibn Sina Hospital (KW)
- Kuwait Cancer Control Center (KW)
- Corresponding author
- Rybak, Jeffrey M.
- Rogers, P. David
- ORCID
- Venue
- Clinical Microbiology and Infection
- Publisher
- Elsevier BV
- Published
- 2022-06
- Volume
- 28
- Issue
- 6
- Pages
- 838-843
- ISSN
- 1198-743X (ISSN-L)
- PMC
- PMC9467277
- OpenAlex
- W4213354765
- Cited by
- 120
- References
- 21
- Citations by year
- 2026: 19 · 2025: 41 · 2024: 26 · 2023: 24 · 2022: 9 · 2021: 1
- FWCI
- 4.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Clinical Microbiology and Infection (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI058145)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Candida auris, amphotericin B resistance, ERG6, sterol methyltransferase, antifungal resistance mechanisms, ergosterol biosynthesis, multidrug-resistant fungi
- MeSH terms
- Candida auris, Amphotericin B, Antifungal Agents, Humans, Microbial Sensitivity Tests, Sterols
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