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

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

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