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Beyond the plasma membrane disruption: Novel antifungal mechanism of Neosartorya (Aspergillus) fischeri antifungal protein 2 in Candida albicans

ABSTRACT: Candida albicans is the most prevalent human pathogenic fungus, responsible for drug-resistant and fatal invasive infections which show an increasing trend in the past two decades. A promising new therapeutic approach involves NFAP2, an antifungal protein secreted by Neosartorya (Aspergillus) fischeri. NFAP2 exhibits potent antifungal activity on both planktonic and biofilm-forming Candida cells in vitro and in vivo. Despite this promising feature,the exact antifungal mechanism of NFAP2 remains in the shadow which hampers its therapeutic application. Based on our recent observations, we suppose that NFAP2 is taken up by Candida cells, and has a long-term growth-slowing effect. Our objective was to understand the molecular mechanism of the long-term growth slowing effect of NFAP2 in C. albicans, therefore the transcriptome of the NFAP2-treated (below the minimum inhibitory concentration) C. albicans SC5314 cultures was compared to that of the untreated ones.The transcriptional responses to NFAP2 were further characterized using functional enrichment analyses of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways.

ORGANISM(S): Candida albicans

PROVIDER: GSE290357 | GEO | 2025/03/03

REPOSITORIES: GEO

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Project description:Sampangine, a plant-derived alkaloid found in the Annonaceae family, exhibits strong inhibitory activity against the opportunistic fungal pathogens Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. In the present study, transcriptional profiling experiments coupled with the analysis of mutants were performed in an effort to elucidate its mechanism of action. Using Saccharomyces cerevisiae as a model organism, we show that sampangine produces a transcriptional response indicative of hypoxia, altering the expression of genes known to respond to low oxygen conditions. Several additional lines of evidence obtained suggest that these responses could involve effects on heme. First, the hem1 deletion mutant lacking the first enzyme in the heme biosynthetic pathway showed increased sensitivity to sampangine, and exogenously supplied hemin partially rescued the inhibitory activity of sampangine in wild-type cells. In addition, heterozygous mutants with deletions in genes involved in five out of eight steps in the heme biosynthetic pathway showed increased susceptibility to sampangine. Furthermore, spectral analysis of pyridine extracts indicated significant accumulation of free porphyrins in sampangine-treated cells. Transcriptional profiling experiments were also performed in C. albicans to investigate the response of a pathogenic fungal species to sampangine. Taking into account the known differences in the physiological responses of C. albicans and S. cerevisiae to low oxygen, significant correlations were observed between the two transcription profiles suggestive of heme-related defects. Our results indicate that the antifungal activity of the plant alkaloid sampangine is due, at least in part, to perturbations in the biosynthesis or metabolism of heme. GSE10073: Gene expression response to the antifungal compound sampangine in S. cerevisiae GSE10075: Gene expression response to the antifungal compound sampangine in C. albicans Keywords: SuperSeries Refer to individual Series

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Beyond the plasma membrane disruption: Novel antifungal mechanism of Neosartorya (Aspergillus) fischeri antifungal protein 2 in Candida albicans

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