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Role of the transcription factors Tac1a and Tac1b in azole resistance in Candida auris

ABSTRACT: Candida auris (Candidozyma auris) is a yeast pathogen that poses a public health threat because of its ability to develop antifungal resistance. Notably, most C. auris isolates are resistant to fluconazole. The efflux pump Cdr1 is a key contributor of azole resistance in C. auris. In C. albicans, Cdr1 is regulated by the transcription factor Tac1, which has two orthologs in C. auris (Tac1a and Tac1b). While the role of Tac1b has been described, little is known about Tac1a. In this study, we characterized the respective roles of Tac1a and Tac1b in azole resistance. To investigate their transcriptional regulation and binding targets, we performed RNA sequencing and ChEC-seq (Chromatin endogenous cleavage sequencing) for both transcription factors. RNA sequencing was carried out by comparing hyperactivated mutants (TAC1a-HA or TAC1b-HA) with the wild-type strain IV.1. ChEC-seq was performed in strains carrying endogenous C-terminal MNase fusions (TAC1a-MNase and TAC1b-MNase) and in a control strain expressing ectopically MNase (Free MNase). Both Tac1a and Tac1b mediate azole resistance in C. auris via regulation of Cdr1, with overlapping downstream targets and evidence of autoregulation.

ORGANISM(S): Candidozyma auris

PROVIDER: GSE307436 | GEO | 2025/09/13

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE307436_Tac1a_10min.bw	Other
	GSE307436_Tac1a_10min_control.bw	Other
	GSE307436_Tac1b_10min.bw	Other
	GSE307436_Tac1b_10min_control.bw	Other

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Genome-wide expression and location analyses of the Candida albicans Tac1p regulon

Project description:A major mechanism of azole resistance in Candida albicans is the over-expression of the genes encoding the ABC transporters Cdr1p and Cdr2p. Constitutive over-expression of these efflux pumps is due to mutations in the gene encoding Tac1p, resulting in hyperactivity of this zinc cluster transcription factor. In order to identify the transcriptional targets of Tac1p, we examined four matched sets of clinical isolates representing the development of CDR1- and CDR2-mediated azole resistance, using gene expression profiling analysis. We identified 31 genes that were consistently up-regulated with CDR1 and CDR2, including TAC1 itself, as well as 12 consistently down-regulated genes. When a resistant strain deleted for TAC1 was similarly examined, the expression of almost all of these genes was returned to levels similar to those in the matched azole-susceptible isolate. Keywords: gene expression profiling Four clinical match isolates (azole susceptible and resistant) were grown as three independent replicates for each set to mid-log phase. A TAC1 knockout derived from resistant isolate 5674 was also grown as three independent replicates. Each resistant isolate was compared to its susceptible parent, and the TAC1 knockout was compared to the susceptible parent (5457) of the resistant isolate, 5674.

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Project description:Objective: Candida auris has emerged as a fungal pathogen of particular concern owing in part to its propensity to exhibit antifungal resistance, especially to the commonly prescribed antifungal fluconazole. In this work we aimed to determine how mutations in the transcription factor gene TAC1B, which are common among resistant isolates and confer fluconazole resistance, exert this effect. Methods: Selected TAC1B mutations from clinical isolates were introduced into a susceptible isolate and reverted to the wild-type sequence in select clinical isolates using CRISPR Cas9 gene editing. Disruption mutants were likewise generated for select genes of interest. TAC1B mutants were subjected to transcriptional profiling by RNA-seq, and relative expression of specific genes of interest was determined by qRT-PCR. Antifungal susceptibilities were determined by modified CLSI broth microdilution. Results: TAC1B mutations leading to A640V, A657V, and F862_N866del conferred fluconazole resistance, as well as increased resistance to other triazoles, when introduced into a susceptible isolate. RNA-seq revealed that the ATP-Binding Cassette (ABC) transporter gene CDR1 as well as the Major Facilitator Superfamily (MFS) transporter gene MDR1 were both up-regulated by these TAC1B mutations. Disruption of CDR1 greatly abrogated resistance in strains with TAC1B mutations whereas disruption of MDR1 had little to no effect. However, disruption of both CDR1 and MDR1 resulted in an additional reduction in resistance as compared to disruption of either gene alone. Conclusion: TAC1B mutations leading to A640V, A657V, and F862_N866del all result in increased resistance to fluconazole and other triazole antifungals, and increased expression of both CDR1 and MDR1 in C. auris. CDR1 is the primary driver of resistance conferred by these TAC1B mutations.

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