fr-900848 and Disease-Models--Animal

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.

Topics: Animals; Antifungal Agents; Cell Proliferation; Disease Models, Animal; Fermentation; Genes, Reporter; Glycosylphosphatidylinositols; Glycosyltransferases; HCT116 Cells; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Inhibitory Concentration 50; K562 Cells; Lung; Male; Mice; Mice, Inbred ICR; Mucorales; Multigene Family; Polyketides; Rhizopus; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins