Jerveratrum-Type Steroidal Alkaloids Inhibit β-1,6-Glucan Biosynthesis in Fungal Cell Walls

• Published in: Microbiology spectrum Vol. 10; no. 1; p. e0087321
• Main Authors: Kubo, Karen, Itto-Nakama, Kaori, Ohnuki, Shinsuke, Yashiroda, Yoko, Li, Sheena C, Kimura, Hiromi, Kawamura, Yumi, Shimamoto, Yasuhiro, Tominaga, Ken-Ichi, Yamanaka, Daisuke, Adachi, Yoshiyuki, Takashima, Shinichiro, Noda, Yoichi, Boone, Charles, Ohya, Yoshikazu
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 23.02.2022
• Subjects: 6-glucan; Alkaloids - isolation & purification; Alkaloids - pharmacology; antifungal; Antifungal Agents - isolation & purification; Antifungal Agents - pharmacology; Antimicrobial Chemotherapy; beta-Glucans - metabolism; Candida - drug effects; Candida - genetics; Candida - metabolism; Cell Wall - drug effects; Cell Wall - metabolism; Fungi - drug effects; Fungi - genetics; Fungi - metabolism; Humans; jervine; Kre6; Mycoses - microbiology; Plant Extracts - isolation & purification; Plant Extracts - pharmacology; Research Article; Skn1; Veratrum - chemistry; β-1; antifungal; 6-glucan; Candida; jervine; Kre6; β-1; Skn1
• ISSN: 2165-0497; 2165-0497
• DOI: 10.1128/spectrum.00873-21

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.