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Clin Microbiol Infect DOI:10.1016/j.cmi.2021.11.024

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

Publication TypeJournal Article
Year of Publication2021
AuthorsRybak, JM, Barker, KS, Muñoz, JF, Parker, JE, Ahmad, S, Mokaddas, E, Abdullah, A, Elhagracy, RS, Kelly, SL, Cuomo, CA, P Rogers, D
JournalClin Microbiol Infect
Date Published2021 Dec 13
ISSN1469-0691
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.

DOI10.1016/j.cmi.2021.11.024
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/34915074?dopt=Abstract

Alternate JournalClin Microbiol Infect
PubMed ID34915074