pH-Dependant Antifungal Activity of Valproic Acid against the Human Fungal Pathogen Candida albicans.
pH-Dependant Antifungal Activity of Valproic Acid against the Human Fungal Pathogen Candida albicans.
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DOI：
10.3389/fmicb.2017.01956
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发表时间：
2017
影响因子：
5.2
通讯作者：
Sellam A
中科院分区：
文献类型：
--
作者：
Chaillot J;Tebbji F;García C;Wurtele H;Pelletier R;Sellam A
目前的抗真菌药物存在一些局限性，包括毒性、出现耐药性以及在低pH值下疗效下降，这些都是人类阴道表面的典型特征。在此，我们发现抗精神病药物丙戊酸(VPA)在与阴道相似的pH条件下，对敏感和耐药的白色念珠菌都显示出很强的抗真菌活性。VPA具有较强的抗生物被膜作用，可减轻白色念珠菌对阴道上皮细胞的损伤。我们还发现VPA与烯丙胺抗真菌药特比奈芬有协同作用。我们进行了一项化学遗传学筛选，以描绘白色念珠菌对VPA敏感的生物学过程，并发现耐受VPA需要与液泡相关的基因。共聚焦荧光活细胞成像显示，VPA改变了空泡的完整性，并支持一个空泡改变有助于抗真菌活性的模型。综上所述，本研究提示VPA可作为一种有效的抗真菌药物用于治疗外阴阴道念珠菌病。
Current antifungal drugs suffer from limitations including toxicity, the emergence of resistance and decreased efficacy at low pH that are typical of human vaginal surfaces. Here, we have shown that the antipsychotic drug valproic acid (VPA) exhibited a strong antifungal activity against both sensitive and resistant Candida albicans in pH condition similar to that encountered in vagina. VPA exerted a strong anti-biofilm activity and attenuated damage of vaginal epithelial cells caused by C. albicans. We also showed that VPA synergizes with the allylamine antifungal, Terbinafine. We undertook a chemogenetic screen to delineate biological processes that underlies VPA-sensitivity in C. albicans and found that vacuole-related genes were required to tolerate VPA. Confocal fluorescence live-cell imaging revealed that VPA alters vacuole integrity and support a model where alteration of vacuoles contributes to the antifungal activity. Taken together, this study suggests that VPA could be used as an effective antifungal against vulvovaginal candidiasis.