Journal Article

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

Fuchs, Florian, Richard, Etienne, Estoppey, David, Tao, Jianshi, Hoepfner, Dominic, Weber, Eric, Studer, Christian, Hunziker, Jürg, Ibrahim, Ashraf S., Aust, Thomas, Riedl, Ralph, Prindle, Vivian, Pistorius, Dominik, Fu, Yue, Petersen, Frank, Schuierer, Sven, Grandjean, Frederic, Mihalic, Manuel, Memmert, Klaus, Roggo, Silvio

2020

Overview

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. Biosynthesis of glycosylphosphatidylinositol (GPI) is essential for the integrity of the fungal cell wall. Here, the authors show that the natural product jawsamycin inhibits GPI biosynthesis by targeting a subunit of the fungal UDP-glycosyltransferase, and displays pronounced activity against pathogenic fungi of the order Mucorales.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 38/70 / 38/77 / 42/40 / 45/47 / 45/70 / 49/47 / 631/154/555 / 631/326/193 / 631/326/22/1292 / 631/326/421 / 64/60 / Anchoring / Animals / Antifungal activity / Antifungal agents / Antifungal Agents - pharmacology / Biosynthesis / Cell Proliferation / Cell walls / Disease Models, Animal / Displays / Fermentation / Fungi / Fungicides / Genes, Reporter / Glycosylphosphatidylinositol / Glycosylphosphatidylinositols - biosynthesis / Glycosyltransferase / Glycosyltransferases - antagonists & inhibitors / HCT116 Cells / Hep G2 Cells / Homology / Humanities and Social Sciences / Humans / Hydrogen-Ion Concentration / Inhibitors / Inhibitory Concentration 50 / Integrity / K562 Cells / Lung - microbiology / Male / Mice / Mice, Inbred ICR / Mucorales / Mucormycosis / multidisciplinary / Multigene Family / Natural products / Polyketides - pharmacology / Proteins / Reporter gene / Rhizopus / Saccharomyces cerevisiae / Saccharomyces cerevisiae Proteins - antagonists & inhibitors / Science / Science (multidisciplinary) / Selectivity