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

Fu, Yue and Estoppey, David and Roggo, Silvio and Pistorius, Dominik and Fuchs, Florian and Studer, Christian and Ibrahim, Ashraf S and Aust, Thomas and Grandjean, Frederic and Mihalic, Manuel and Memmert, Klaus and Prindle, Vivian and Richard, Etienne and Riedl, Ralph and Schuierer, Sven and Weber, Eric and Hunziker, Juerg and Petersen, Frank and Tao, Jianshi and Hoepfner, Dominic (2020) Jawsamycin exhibits in vivo antifungal properties by inhibiting Spt14/Gpi3-mediated biosynthesis of glycosylphosphatidylinositol. Nature Communications, 11 (1). ISSN 20411723

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.

Item Type: Article
Keywords: Jawsamycin, GPI, PIG-A, GPI3, Target Identification, Antifungal, Natural Product
Date Deposited: 11 Aug 2020 00:45
Last Modified: 11 Aug 2020 00:45
URI: https://oak.novartis.com/id/eprint/40847

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