Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
AIST-UTokyo Advanced Operando-Measurement Technology Open Innovation Laboratory (OPERANDO-OIL), National Institute of Advanced Industrial Science and Technology (AIST), Kashiwa, Chiba, Japan.
Microbiol Spectr. 2022 Feb 23;10(1):e0087321. doi: 10.1128/spectrum.00873-21. Epub 2022 Jan 12.
The limited number of available effective agents necessitates the development of new antifungals. We report that jervine, a jerveratrum-type steroidal alkaloid isolated from Veratrum californicum, has antifungal activity. Phenotypic comparisons of cell wall mutants, K1 killer toxin susceptibility testing, and quantification of cell wall components revealed that β-1,6-glucan biosynthesis was significantly inhibited by jervine. Temperature-sensitive mutants defective in essential genes involved in β-1,6-glucan biosynthesis, including , , , , and , were hypersensitive to jervine. In contrast, point mutations in or its paralog produced jervine resistance, suggesting that jervine targets Kre6 and Skn1. Jervine exhibited broad-spectrum antifungal activity and was effective against human-pathogenic fungi, including Candida parapsilosis and Candida krusei. It was also effective against phytopathogenic fungi, including Botrytis cinerea and Puccinia recondita. Jervine exerted a synergistic effect with fluconazole. Therefore, jervine, a jerveratrum-type steroidal alkaloid used in pharmaceutical products, represents a new class of antifungals active against mycoses and plant-pathogenic fungi. Non-Candida albicans species (NCAC) are on the rise as a cause of mycosis. Many antifungal drugs are less effective against NCAC, limiting the available therapeutic agents. Here, we report that jervine, a jerveratrum-type steroidal alkaloid, is effective against NCAC and phytopathogenic fungi. Jervine acts on Kre6 and Skn1, which are involved in β-1,6-glucan biosynthesis. The skeleton of jerveratrum-type steroidal alkaloids has been well studied, and more recently, their anticancer properties have been investigated. Therefore, jerveratrum-type alkaloids could potentially be applied as treatments for fungal infections and cancer.
可用的有效药物数量有限，这就需要开发新的抗真菌药物。我们报告称，从加利福尼亚藜芦中分离出的藜芦嗪是一种杰维菌素型甾体生物碱，具有抗真菌活性。细胞壁突变体的表型比较、K1 杀伤毒素敏感性测试以及细胞壁成分的定量分析表明，β-1,6-葡聚糖生物合成被藜芦嗪显著抑制。参与β-1,6-葡聚糖生物合成的必需基因的温度敏感突变体缺陷，包括 、 、 、 、和 ，对藜芦嗪高度敏感。相比之下，在 或其同源物 中的点突变产生了藜芦嗪抗性，表明藜芦嗪的靶标是 Kre6 和 Skn1。藜芦嗪表现出广谱抗真菌活性，对包括近平滑念珠菌和克柔念珠菌在内的人类致病性真菌有效，对包括灰葡萄孢菌和小麦条锈病菌在内的植物病原真菌也有效。藜芦嗪与氟康唑具有协同作用。因此，作为药物使用的杰维菌素型甾体生物碱代表了一类新的抗真菌药物，对真菌病和植物病原真菌有效。非白念珠菌（NCAC）作为真菌病的病因呈上升趋势。许多抗真菌药物对 NCAC 的效果较差，限制了可用的治疗药物。在这里，我们报告称，杰维菌素，一种杰维菌素型甾体生物碱，对 NCAC 和植物病原真菌有效。藜芦嗪作用于 Kre6 和 Skn1，它们参与β-1,6-葡聚糖生物合成。杰维菌素型甾体生物碱的骨架已经得到了很好的研究，最近，它们的抗癌特性也得到了研究。因此，杰维菌素型生物碱可能被应用于真菌感染和癌症的治疗。
