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Annals of Translational Medicine · 2020 · IF 3.297

Teasaponin suppresses Candida albicans filamentation by reducing the level of intracellular cAMP

Ying Li,Mingzhu Shan,Shihui Li,Yuechen Wang,Huan Yang,Ying Chen,Bing Gu,Zuobin Zhu

Background Candidiasis has long been a threat to human health, but cytotoxicity and resistance always block the usefulness of antifungal agents. The ability to switch between yeast and hypha is one of the most discussed virulence trait attributes of the human pathogenic fungus Candida albicans . The morphological transition provides a novel target for developing antifungal drugs. The aim of the present study was to explore the activity and mechanism of teasaponin (TS), a generally regarded as safe natural product, in inhibiting filamentation of C. albicans , hoping to provide an experimental basis for its clinical application. Methods The effect of TS on filamentation and biofilm formation of C. albicans was evaluated by XTT reduction assay and microscopy. The level of intracellular cAMP was measured to further explore the underlying mechanism. In addition, cytotoxicity of TS was evaluated by using MTT assay in vitro and Caenorhabditis elegans model in vivo . The potential of TS-resistance induction was tested by a serial passage experiment. Results TS displayed a moderate antifungal activity against the wild type, efflux pump mutant and multi-resistance C. albicans strains, and could effectively retard filamentation and biofilm formation with a low MIC value. Further mechanism investigation revealed that the reduced cAMP level inhibited filamentation and biofilm formation. In addition, TS showed no significant cytotoxicity in vitro or in vivo , and had little potential to develop resistance during long-time induction. Conclusions Our work evaluated the antifungal activity of TS against filamentation and biofilms formation of C. albicans and disclosed the underlying mechanism, which might provide useful clues for the potential clinical application of TS in fighting clinical fungal infections by targeting the virulence factors.

研究领域: 微生物学 · 药理学 · 分子生物学
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Cell Chemical Biology · 2023 · IF 8.6

Characterization of an allosteric inhibitor of fungal-specific C-24 sterol methyltransferase to treat Candida albicans infections

Xueyang Jin,Xuben Hou,Xue Wang,Ming Zhang,Jinyao Chen,Minghui Song,Jiaozhen Zhang,Hongbo Zheng,Wenqiang Chang,Hongxiang Lou

Summary Filamentation is an important virulence factor of the pathogenic fungus Candida albicans . The abolition of Candida albicans hyphal formation by disrupting sterol synthesis is an important concept for the development of antifungal drugs with high safety. Here, we conduct a high-throughput screen using a C . albicans strain expressing green fluorescent protein-labeled Dpp3 to identify anti-hypha agents by interfering with ergosterol synthesis. The antipyrine derivative H55 is characterized to have minimal cytotoxicity and potent inhibition of C . albicans hyphal formation in multiple cultural conditions. H55 monotherapy exhibits therapeutic efficacy in mouse models of azole-resistant candidiasis. H55 treatment increases the accumulation of zymosterol , the substrate of C-24 sterol methyltransferase (Erg6). The results of enzyme assays, photoaffinity labeling , molecular simulation, mutagenesis , and cellular thermal shift assays support H55 as an allosteric inhibitor of Erg6. Collectively, H55, an inhibitor of the fungal-specific enzyme Erg6, holds potential to treat C . albicans infections.

CAS / MDL: 106-24-1 78330-21-9
研究领域: 微生物学 · 药理学 · 分子生物学
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