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

Autor:	Fu Y; Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA, 92121, USA., Estoppey D; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Roggo S; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Pistorius D; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Fuchs F; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Studer C; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Ibrahim AS; The Lundquist Institute for Biomedical Innovations at Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance, CA, 90502, USA.; David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA., Aust T; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Grandjean F; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Mihalic M; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Memmert K; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Prindle V; Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA, 92121, USA., Richard E; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Riedl R; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Schuierer S; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Weber E; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Hunziker J; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Petersen F; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland., Tao J; Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA, 92121, USA. jtao@gnf.org., Hoepfner D; Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland. dominic.hoepfner@novartis.com.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Jul 07; Vol. 11 (1), pp. 3387. Date of Electronic Publication: 2020 Jul 07.
DOI:	10.1038/s41467-020-17221-5
Abstrakt:	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.
Databáze:	MEDLINE
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