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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Authors | 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 |
Journal | Nature communications
(Nat Commun)
Vol. 11
Issue 1
Pg. 3387
(07 07 2020)
ISSN: 2041-1723 [Electronic] England |
PMID | 32636417
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Antifungal Agents
- Glycosylphosphatidylinositols
- Polyketides
- SPT14 protein, S cerevisiae
- Saccharomyces cerevisiae Proteins
- jawsamycin
- Glycosyltransferases
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Topics |
- Animals
- Antifungal Agents
(pharmacology)
- Cell Proliferation
- Disease Models, Animal
- Fermentation
- Genes, Reporter
- Glycosylphosphatidylinositols
(biosynthesis)
- Glycosyltransferases
(antagonists & inhibitors)
- HCT116 Cells
- Hep G2 Cells
- Humans
- Hydrogen-Ion Concentration
- Inhibitory Concentration 50
- K562 Cells
- Lung
(microbiology)
- Male
- Mice
- Mice, Inbred ICR
- Mucorales
- Multigene Family
- Polyketides
(pharmacology)
- Rhizopus
- Saccharomyces cerevisiae
- Saccharomyces cerevisiae Proteins
(antagonists & inhibitors)
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