Natural Enfumafungin Analogues from Hormonema carpetanum and Their Antifungal Activities

Ibrexafungerp, an inhibitor of fungal beta-(1,3)-d-glucan synthase, represents the first new class of antifungals to be approved in the last 20 years. Ibrexafungerp is a semisynthetic derivative of the naturally occurring triterpene glycoside enfumafungin. In order to search for new analogues of enfumafungin and to probe its biosynthesis, we undertook a reinvestigation of Hormonema carpetanum, which led to the isolation of two new analogues, enfumafungins B and C, together with enfumafungin. Due to the presence of a hemiacetal moiety in the structure, the enfumafungins appear as a mixture of two interconverting epimers during both the purification process and NMR data acquisition. The structure elucidation, including the differentiation of 25S* and 25R* epimers, was completed by combined analyses of NMR and MS spectroscopic data. The discovery of enfumafungins B and C may have implications for enfumafungin biosynthesis. The antifungal activity of enfumafungins B and C was significantly lower than that of enfumafungin, suggesting that the C-2 substituents and the C-19 carboxy acid are important for activity. Molecular docking simulations revealed significant hydrogen bond interactions between enfumafungins and beta-(1,3)-d-glucan synthase, which may be useful for developing new antifungal agents.

Automated summary

Ibrexafungerp, a new class of antifungal drugs, is an inhibitor of fungal beta-(1,3)-d-glucan synthase and has been approved in the last 20 years. It is a semisynthetic derivative of enfumafungin, a naturally occurring triterpene glycoside. Researchers discovered two new analogues, enfumafungins B and C, as well as enfumafungin, by investigating Hormonema carpetanum. The structures of enfumafungins were determined through NMR and MS spectroscopic data analysis. Enfumafungins B and C showed lower antifungal activity compared to enfumafungin, indicating the importance of the C-2 substituents and the C-19 carboxy acid for activity. Molecular docking simulations revealed significant hydrogen bond interactions between enfumafungins and beta-(1,3)-d-glucan synthase, which may aid in the development of new antifungal agents.