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Expression analysis of novel and known antifungal drugs using S. cerevisiae as a model

ABSTRACT: A systematic approach allowing the identification of the molecular way of action of novel potential drugs still represents the golden-tool for drug-discovery researchers. While high-throughput screening technologies of large libraries is now well established, the assessment of the drug targets and mechanism of action is still under development. Taking advantage of the yeast model Saccharomyces cerevisiae, we herein applied BarSeq, a Next Generation Sequencing based method to the analysis of both haploinsufficiency and homozygous fitness effects of a novel antifungal drug compared to the well-known antifungal, ketoconazole. Integrative bioinformatic analysis of BarSeq, whole genome expression analysis and classical biological assays identified the target and cell pathways affected by the novel antifungal. Confirmation of the effects observed in the yeast model as well as in pathogenic fungi further demonstrated the reliability of the multi-sided approach and the novelty of the targets and mode of action of the new class of molecules studied that thus represent a valuable source of novel antifungals.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE42418 | GEO | 2016/12/30

SECONDARY ACCESSION(S): PRJNA181366

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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Expression analysis of novel and known antifungal drugs using S. cerevisiae as a model

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