RT Journal Article
SR Electronic
T1 <em>In vivo</em> emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in <em>Candida auris</em>
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.10.08.463721
DO 10.1101/2021.10.08.463721
A1 Jeffrey M. Rybak
A1 Katherine S. Barker
A1 José F. Muñoz
A1 Josie E. Parker
A1 Suhail Ahmad
A1 Eiman Mokaddas
A1 Aneesa Abdullah
A1 Rehab S. Elhagracy
A1 Steve L. Kelly
A1 Christina A. Cuomo
A1 P. David Rogers
YR 2021
UL http://biorxiv.org/content/early/2021/10/09/2021.10.08.463721.abstract
AB Candida auris has emerged as a healthcare-associated and multidrug-resistant fungal pathogen of great clinical concern. While as much as 50% of C. auris clinical isolates are reported to be resistant to amphotericin B, to date, no mechanisms contributing to this resistance have been identified. We report here mutations in the C. auris sterol-methyltransferase gene, ERG6, as the first identified mechanism of amphotericin B resistance in this emerging pathogen and describe the clinical case in which this high-level amphotericin B resistance was acquired in vivo during therapy. Whole genome sequencing revealed the four C. auris isolates obtained from this single patient case to be genetically related and identified a mutation in ERG6 as being associated with amphotericin B resistance. Cas9-mediated genetic manipulations confirmed this mutation alone to confer a &gt;32-fold increase in amphotericin B resistance, and comprehensive sterol profiling revealed an abrogation of ergosterol biosynthesis and a corresponding accumulation of cholesta-type sterols in isolates and strains harboring the clinically derived ERG6 mutation. Together these findings represent the first significant step forward in the understanding of clinical amphotericin B resistance in C. auris.Competing Interest StatementThe authors have declared no competing interest.