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

ABSTRACT: 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

ORGANISM(S): Candida albicans

PROVIDER: GSE8727 | GEO | 2008/03/15

SECONDARY ACCESSION(S): PRJNA101981

REPOSITORIES: GEO

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Project description:Azole antifungal agents such as fluconazole exhibit fungistatic activity against Candida albicans. Strategies to enhance azole antifungal activity would be therapeutically appealing. In an effort to identify transcriptional pathways that influence fluconazole susceptibility, we sought to identify transcription factors (TFs) involved in this process. From a collection of C. albicans strains disrupted for genes encoding TFs (Homann et al., PLoS Genet. 2009;5:e1000783), four exhibited a marked reduction in minimum fungicidal concentration (MFC) in both RPMI and YPD media. One of these, UPC2, has been previously characterized with regard to its role in azole susceptibility. Of mutants representing the three remaining TF genes of interest, one (CAS5) was unable to recover from fluconazole exposure at concentrations as low as 2 M-BM-5g/mL after 72 hours in YPD medium. This mutant also showed reduced susceptibility and a clear zone of inhibition by Etest, was unable to grow on solid media containing 10 M-BM-5g/mL fluconazole, and exhibited increased susceptibility by time-kill analysis. CAS5 disruption in highly azole-resistant clinical isolates exhibiting multiple resistance mechanisms did not alter susceptibility. However, CAS5 disruption in strains with specific resistance mutations in ergosterol biosynthesis or efflux pumps resulted in a moderate reduction in MIC and MFC. Genome-wide transcriptional analysis was performed in the presence of fluconazole and was consistent with the suggested role of CAS5 in cell wall organization while also suggesting a role in iron transport and homeostasis. These findings suggest that Cas5 regulates a transcriptional network that influences susceptibility of C. albicans to fluconazole. Further delineation of this transcriptional network may identify targets for potential co-therapeutic strategies to enhance the activity to the azole class of antifungals. We examined the genome-wide gene expression profiles of the wild-type parent strain SC5314 and its cas5M-NM-^T/M-NM-^T derivative in response to fluconazole in order to identify genes whose expression in response to fluconazole is influenced by Cas5.

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

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