Work

Mechanisms of aureobasidin A inhibition and drug resistance in a fungal IPC synthase complex

Year: 2025

Type: article

Abstract: The enzyme inositol phosphorylceramide (IPC) synthase is essential for survival and virulence in fungi, while absent in mammals, thus representing a potential target for antifungal treatments. Aureobasidin A (AbA), a natural cyclic peptide, displays antifungal activity and inhibits IPC synthase, but the precise molecular mechanism remains unclear. Here, we present the cryo-EM structure of the Saccharomyces cerevisiae IPC synthase, composed of catalytic subunit Aur1 and regulatory subunit Kei1, in its AbA-bound state. The complex is resolved as a dimer of Aur1-Kei1 heterodimers, with Aur1 mediating homodimerization. AbA occupies a predominantly hydrophobic pocket in the catalytic core domain of each Aur1 subunit, blocking the entry of both substrates. Mutations conferring AbA resistance cluster near the AbA-binding site, thus interfering with AbA binding. Our study lays a foundation for the development of therapeutic drugs targeting fungal IPC synthase. The antifungal peptide aureobasidin A (AbA) inhibits a fungal enzyme, IPC synthase, through unclear mechanisms. Here, the authors present the cryo-EM structure of the yeast IPC synthase bound to AbA, revealing interactions between catalytic and regulatory subunits and showing how mutations conferring AbA resistance interfere with AbA binding.

Source: Nature Communications

DOI: 10.1038/s41467-025-60423-y

Authors: Xinyue Wu, Xin Gong, Tian Xie

Institution: Southern University of Science and Technology

Language: English

Topic: Fungal and yeast genetics research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $6,990

Funders: National Natural Science Foundation of China, Science, Technology and Innovation Commission of Shenzhen Municipality, Southern University of Science and Technology