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In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris

Jeffrey M. Rybak, Katherine S. Barker, José F. Muñoz, Josie Parker, Suhail Ahmad, Eiman Mokaddas, Aneesa Abdullah, Rehab S. Elhagracy, Steven Kelly Orcid Logo, Christina A. Cuomo, P. David Rogers

Clinical Microbiology and Infection, Volume: 28, Issue: 6, Pages: 838 - 843

Swansea University Authors: Josie Parker, Steven Kelly Orcid Logo

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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...

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Published in: Clinical Microbiology and Infection
ISSN: 1198-743X
Published: Elsevier BV 2022
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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.
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