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

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, Etienne Richard, Ralph Riedl, Sven Schuierer, Eric Weber, Jürg Hunziker, Frank Petersen, Jianshi Tao () and Dominic Hoepfner ()
Additional contact information
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
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

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17221-5

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