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

Xinyue Wu, Xin Gong () and Tian Xie ()
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Xinyue Wu: Southern University of Science and Technology
Xin Gong: Southern University of Science and Technology
Tian Xie: Southern University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60423-y

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