Mutations in TAC1B: a novel genetic determinant of clinical fluconazole resistance in Candida auris

Rybak, Jeffrey M., Muñoz, José F., Barker, Katherine S., Parker, Josie E., Esquivel, Brooke D., Berkow, Elizabeth L., Lockhart, Shawn R., Gade, Lalitha, Palmer, Glen E., White, Theodore C., Kelly, Steve L., Cuomo, Christina A., Rogers, P. David and Berman, Judith 2020. Mutations in TAC1B: a novel genetic determinant of clinical fluconazole resistance in Candida auris. mBio 11 (3) , e00365-20. 10.1128/mBio.00365-20

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Abstract

Candida auris has emerged as a multidrug-resistant pathogen of great clinical concern. Approximately 90% of clinical C. auris isolates are resistant to fluconazole, the most commonly prescribed antifungal agent, and yet it remains unknown what mechanisms underpin this fluconazole resistance. To identify novel mechanisms contributing to fluconazole resistance in C. auris, fluconazole-susceptible C. auris clinical isolate AR0387 was passaged in media supplemented with fluconazole to generate derivative strains which had acquired increased fluconazole resistance in vitro. Comparative analyses of comprehensive sterol profiles, [3H]fluconazole uptake, sequencing of C. auris genes homologous to genes known to contribute to fluconazole resistance in other species of Candida, and relative expression levels of C. auris ERG11, CDR1, and MDR1 were performed. All fluconazole-evolved derivative strains were found to have acquired mutations in the zinc-cluster transcription factor-encoding gene TAC1B and to show a corresponding increase in CDR1 expression relative to the parental clinical isolate, AR0387. Mutations in TAC1B were also identified in a set of 304 globally distributed C. auris clinical isolates representing each of the four major clades. Introduction of the most common mutation found among fluconazole-resistant clinical isolates of C. auris into fluconazole-susceptible isolate AR0387 was confirmed to increase fluconazole resistance by 8-fold, and the correction of the same mutation in a fluconazole-resistant isolate, AR0390, decreased fluconazole MIC by 16-fold. Taken together, these data demonstrate that C. auris can rapidly acquire resistance to fluconazole in vitro and that mutations in TAC1B significantly contribute to clinical fluconazole resistance.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	American Society for Microbiology
ISSN:	2161-2129
Date of First Compliant Deposit:	8 July 2022
Date of Acceptance:	13 April 2020
Last Modified:	04 May 2023 10:43
URI:	https://orca.cardiff.ac.uk/id/eprint/151170

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