title: Bisbibenzyls, a new type of antifungal agent, inhibit morphogenesis switch and biofilm formation through upregulation of DPP3 in Candida albicans.
abstract: The yeast-to-hypha transition plays a crucial role in the pathogenesis of C. albicans. Farnesol, a quorum sensing molecule (QSM) secreted by the fungal itself, could prevent the formation of hyphae and subsequently lead to the defect of biofilm formation. The DPP3, encoding phosphatase, is a key gene in regulating farnesol synthesis. In this study, we screened 24 bisbibenzyls and 2 bibenzyls that were isolated from bryophytes or chemically synthesized by using CLSI method for antifungal effect. Seven bisbibenzyls were found to have antifungal effects with IC(80) less than 32 µg/ml, and among them, plagiochin F, isoriccardin C and BS-34 were found to inhibit the hyphae and biofilm formation of C. albicans in a dose-dependent manner. To uncover the underlying relationship between morphogenesis switch and QSM formation, we measured the farnesol production by HPLC-MS and quantified Dpp3 expression by detecting the fluorescent intensity of green fluorescent protein tagged strain using Confocal Laser Scanning microscopy and Multifunction Microplate Reader. The DPP3 transcripts were determined by real-time PCR. The data indicated that the bisbibenzyls exerted antifungal effects through stimulating the synthesis of farnesol via upregulation of Dpp3, suggesting a potential antifungal application of bisbibenzyls. In addition, our assay provides a novel, visual and convenient method to measure active compounds against morphogenesis switch.
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Chang
authors.forename: Bin
authors.initials: B
authors.lastname: Sun
authors.forename: Matthias
authors.initials: M
authors.lastname: Groh
authors.forename: Andreas
authors.initials: A
authors.lastname: Speicher
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Lou
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001632:Bibenzyls / Q000737:chemistry / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D002176:Candida albicans / Q000166:cytology / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D005204:Farnesol / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008858:Microscopy, Phase-Contrast; D009024:Morphogenesis / Q000187:drug effects*; D025282:Mycelium / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000935:Antifungal Agents; D001632:Bibenzyls; D005656:Fungal Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D005204:Farnesol