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

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  • Xinyue Wu

    (Southern University of Science and Technology
    Southern University of Science and Technology)

  • Xin Gong

    (Southern University of Science and Technology
    Southern University of Science and Technology
    Southern University of Science and Technology)

  • Tian Xie

    (Southern University of Science and Technology
    Southern University of Science and Technology)

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.

Suggested Citation

  • Xinyue Wu & Xin Gong & Tian Xie, 2025. "Mechanisms of aureobasidin A inhibition and drug resistance in a fungal IPC synthase complex," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60423-y
    DOI: 10.1038/s41467-025-60423-y
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