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Genome-wide Translational Response of Candida albicans to Fluconazole Treatment

ABSTRACT: Azoles are commonly used for the treatment of fungal infections and the ability of human fungal pathogens to rapidly respond to azole treatment is critical for the development of antifungal resistance. While the role of genetic mutations, chromosomal rearrangements and transcriptional mechanisms in azole resistance has been well-characterized, very little is known about post-transcriptional and translation mechanisms that drive this process. In addition, most previous genome-wide studies have focused on transcriptional responses to azole treatment, and likely serve as an inaccurate proxies due to extensive post-transcriptional and translational regulation. In this study we use ribosome profiling to provide the first picture of the global translational response of a major human fungal pathogen, Candida albicans, to treatment with fluconazole, one of the most widely used azole drugs. We identify sets of genes showing significantly altered translational efficiency (TE), including genes associated with a variety of biological processes such as the cell cycle, DNA repair, cell wall/cell membrane biosynthesis, transport, signaling, DNA- and RNA-binding activities and protein synthesis. Importantly, while there are similarities and differences among gene categories that are regulated by fluconazole at the translational vs. transcriptional levels, we observe very little overlap among individual genes controlled by these mechanisms. Our findings suggest that C. albicans possesses distinct translational mechanisms that are important for the response to antifungal treatment, which could eventually be targeted by novel antifungal therapies.

ORGANISM(S): Candida albicans

PROVIDER: GSE227590 | GEO | 2023/08/05

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.

Project description:In Candida albicans, the transcription factor Upc2 is central to the regulation of ergosterol biosynthesis. UPC2-activating mutations contribute to azole resistance, whereas disruption increases azole susceptibility. In the present study, we investigated the relationship of UPC2 to fluconazole susceptibility, particularly in azole-resistant strains. In addition to the reduced fluconazole MIC previously observed with UPC2 disruption, we observed a lower minimum fungicidal concentration (MFC) for a upc2M-NM-^T/M-NM-^T mutant than for its azole-susceptible parent, SC5314. Moreover, the upc2M-NM-^T/M-NM-^T mutant was unable to grow on a solid medium containing 10 M-BM-5g/ml fluconazole and exhibited increased susceptibility and a clear zone of inhibition by Etest. Time-kill analysis showed higher fungistatic activity against the upc2M-NM-^T/M-NM-^T mutant than against SC5314. UPC2 disruption in strains carrying specific resistance mutations also resulted in reduced MICs and MFCs. UPC2 disruption in a highly azole resistant clinical isolate containing multiple resistance mechanisms likewise resulted in a reduced MIC and MFC. This mutant was unable to grow on a solid medium containing 10 M-BM-5g/ml fluconazole and exhibited increased susceptibility and a clear zone of inhibition by Etest. Time-kill analysis showed increased fungistatic activity against the upc2M-NM-^T/M-NM-^T mutant in the resistant background. Microarray analysis showed attenuated induction by fluconazole of genes involved in sterol biosynthesis, iron transport, or iron homeostasis in the absence of UPC2. Taken together, these data demonstrate that the UPC2 transcriptional network is universally essential for azole resistance in C. albicans and represents an attractive target for enhancing azole antifungal activity. We examined the genome-wide gene expression profiles of the wild-type parent strain SC5314 and its upc2M-NM-^T/M-NM-^T derivative in response to fluconazole in order to identify genes whose expression in response to fluconazole is influenced by Upc2.

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Genome-wide Translational Response of Candida albicans to Fluconazole Treatment

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