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.

糖基磷脂酰肌醇 (GPI) 的生物合成是将蛋白质锚定到质膜所必需的，并且对于真菌细胞壁的完整性至关重要。在这里，我们在酿酒酵母中使用基于报告基因的筛选来发现 GPI 锚定蛋白质的抗真菌抑制剂，并将含寡环丙基的天然产物 jawsamycin (FR-900848) 鉴定为有效的命中。该化合物靶向真菌 UDP-糖基转移酶的催化亚基 Spt14（也称为 Gpi3），这是 GPI 生物合成的第一步，对人类功能同系物 PIG-A 具有良好的选择性。Jawsamycin 在体外对包括毛霉目在内的几种致病真菌表现出抗真菌活性，并且在侵袭性肺毛霉菌病小鼠模型中显示出体内抗真菌活性Rhyzopus delemar感染。我们的结果为开发用于治疗侵袭性真菌感染的 Spt14 抑制剂提供了起点。