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Functional genomic analysis of genes important for Candida albicans fitness in diverse environmental conditions

ABSTRACT: As the limited arsenal of effective antifungals in clinical use is threatened by emerging resistance, the demand for new strategies to combat invasive fungi is urgent. One strategy to expand the therapeutic target space is to identify genes important for pathogen growth in host-relevant environments. Here, we leveraged a pooled functional genomic screening strategy to identify and characterize genes important for fitness of the human fungal pathogen Candida albicans in diverse conditions. Through this approach we identified a novel essential gene with no known Saccharomyces cerevisiae homolog, C1_09670C, and demonstrated that it encodes subunit 3 of replication factor A, Rfa3. Furthermore, we applied robust computational analyses to leverage profile similarity analysis of mutant phenotypes across conditions to identify functionally-coherent gene clusters and predict gene function. Through this approach, we correctly predicted the cell cycle-associated function of C3_06880W, a previously uncharacterized genes required for fitness specifically at elevated temperatures. Protein structure predictions coupled with genetic and biochemical assays confirmed C3_06880W encodes Iml3, a component of the C. albicans kinetochore with key roles in C. albicans virulence in vivo. Overall, this work reveals novel insights into the vulnerabilities of C. albicans.

ORGANISM(S): Candida albicans

PROVIDER: GSE266247 | GEO | 2024/08/07

REPOSITORIES: GEO

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Project description:Fungal infections are a serious health problem in clinics especially in the immune-compromised patient. Disease ranges from widespread superficial infections like vulvovaginal infections to life-threatening systemic candidiasis. Especially for systemic mycoses only a limited arsenal of antifungals is available. The most commonly used classes of antifungal compounds used include azoles, polyenes and echinocandines. Due to emerging resistance to standard therapy and significant side effects and high costs for several antifungals.,there is a medical need for new antifungals in the clinic and general practice. In order to expand the arsenal of compounds with antifungal activities we previously screened a compound library, using a new type of activity-selectivity (AS) assay analysing both the antifungal activity and the compatibility with human cells at the same time. One compound, ((S)-2-(1-aminoisobutyl)-1-(3-chlorobenzyl) benzimidazole (EMC120B12)), showed high antifungal activity against several species of pathogenic yeasts including C. glabrata and C. krusei, species which are highly refractory to antifungals, especially to the commonly used azoles. Here we could show by transcriptional profiling and sterol analysis that the target of this new antifungal compound is the ergosterol pathway. The effects of EMC120B12 on sterol biosynthesis mimic those of fluconazole, strongly indicating that EMC120B12 also targets ERG11 like the azols. But not only the marker sterol 14 methylergosta 8,24(28) dien 3β,6α diol accumulated in C. krusei under EMC120B12 treatment, but also hitherto unknown related sterols. The novel sterols have a 3β,6α diol structure. Furthermore, this is the first time that a benzimidazole structure has been shown to result in a block of the sterol pathway by accumulating marker sterols connected to ERG11 inactivation. In total, three biological replicates were performed. All experiments were performed as dye swaps. Thus, in total 18 arrays have been hybridzed. Hybridization experiments included an untreated reference sample and a sample of cells treated with either ((1S)-1-[1-(3-chlorobenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl-amine) (EMC120B12), Fluconazole or Nocodazole. The array included one technical replicate of each probe.

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Functional genomic analysis of genes important for Candida albicans fitness in diverse environmental conditions

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