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

Nature communications 2020 Jul 07

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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.

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, Etienne Richard, Ralph Riedl, Sven Schuierer, Eric Weber, Jürg Hunziker, Frank Petersen, Jianshi Tao, Dominic Hoepfner. Jawsamycin exhibits in vivo antifungal properties by inhibiting Spt14/Gpi3-mediated biosynthesis of glycosylphosphatidylinositol. Nature communications. 2020 Jul 07;11(1):3387