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Jawsamycin exhibits in vivo antifungal properties by inhibiting Spt14/Gpi3-mediated biosynthesis of glycosylphosphatidylinositol

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Listed:
  • Yue Fu

    (Genomics Institute of the Novartis Research Foundation)

  • David Estoppey

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Silvio Roggo

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Dominik Pistorius

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Florian Fuchs

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Christian Studer

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Ashraf S. Ibrahim

    (The Lundquist Institute for Biomedical Innovations at Harbor-University of California at Los Angeles (UCLA) Medical Center
    David Geffen School of Medicine at UCLA)

  • Thomas Aust

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Frederic Grandjean

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Manuel Mihalic

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Klaus Memmert

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Vivian Prindle

    (Genomics Institute of the Novartis Research Foundation)

  • Etienne Richard

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Ralph Riedl

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Sven Schuierer

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Eric Weber

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Jürg Hunziker

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Frank Petersen

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

  • Jianshi Tao

    (Genomics Institute of the Novartis Research Foundation)

  • Dominic Hoepfner

    (Novartis Institutes for BioMedical Research, Novartis Pharma AG)

Abstract

Biosynthesis of glycosylphosphatidylinositol (GPI) is required for anchoring proteins to the plasma membrane, and is essential for the integrity of the fungal cell wall. Here, we use a reporter gene-based screen in Saccharomyces cerevisiae for the discovery of antifungal inhibitors of GPI-anchoring of proteins, and identify the oligocyclopropyl-containing natural product jawsamycin (FR-900848) as a potent hit. The compound targets the catalytic subunit Spt14 (also referred to as Gpi3) of the fungal UDP-glycosyltransferase, the first step in GPI biosynthesis, with good selectivity over the human functional homolog PIG-A. Jawsamycin displays antifungal activity in vitro against several pathogenic fungi including Mucorales, and in vivo in a mouse model of invasive pulmonary mucormycosis due to Rhyzopus delemar infection. Our results provide a starting point for the development of Spt14 inhibitors for treatment of invasive fungal infections.

Suggested Citation

  • Yue Fu & David Estoppey & Silvio Roggo & Dominik Pistorius & Florian Fuchs & Christian Studer & Ashraf S. Ibrahim & Thomas Aust & Frederic Grandjean & Manuel Mihalic & Klaus Memmert & Vivian Prindle &, 2020. "Jawsamycin exhibits in vivo antifungal properties by inhibiting Spt14/Gpi3-mediated biosynthesis of glycosylphosphatidylinositol," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17221-5
    DOI: 10.1038/s41467-020-17221-5
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    Cited by:

    1. Yidan Xu & Tingting Li & Zixuan Zhou & Jingjing Hong & Yulin Chao & Zhini Zhu & Ying Zhang & Qianhui Qu & Dianfan Li, 2023. "Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Jingjing Hong & Tingting Li & Yulin Chao & Yidan Xu & Zhini Zhu & Zixuan Zhou & Weijie Gu & Qianhui Qu & Dianfan Li, 2024. "Molecular basis of the inositol deacylase PGAP1 involved in quality control of GPI-AP biogenesis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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