Journal article 100 views
In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris
,
Christina A. Cuomo,
P. David Rogers
Clinical Microbiology and Infection, Volume: 28, Issue: 6, Pages: 838 - 843
Swansea University Authors:
Josie Parker, Steven Kelly
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DOI (Published version): 10.1016/j.cmi.2021.11.024
Abstract
ObjectiveCandida 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...
| Published in: | Clinical Microbiology and Infection |
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| ISSN: | 1198-743X |
| Published: |
Elsevier BV
2022
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa59077 |
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| Abstract: |
ObjectiveCandida 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.MethodsWhole-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.ResultsA 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.ConclusionsTogether 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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| Keywords: |
amphotericin B; Candida auris; ERG6; In vivo evolution; Resistance |
| College: |
Swansea University Medical School |
| Funders: |
National Institutes of Health (USA). |
| Issue: |
6 |
| Start Page: |
838 |
| End Page: |
843 |