Invasive fungal infections are accompanied by high mortality rates that range up to 90%. At present, only three different compound classes are available for use in the clinic, and these often suffer from low bioavailability, toxicity, and drug resistance. These issues emphasize an urgent need for novel antifungal agents. Herein, we report the identification of chemically versatile benzamide and picolinamide scaffolds with antifungal properties. Chemogenomic profiling and biochemical assays with purified protein identified Sec14p, the major phosphatidylinositol/phosphatidylcholine transfer protein inSaccharomyces cerevisiae, as the sole essential target for these compounds. A functional variomics screen identified resistance-conferring residues that localized to the lipid-binding pocket of Sec14p. Determination of the X-ray co-crystal structure of a Sec14p-compound complex confirmed binding in this cavity and rationalized both the resistance-conferring residues and the observed structure-activity relationships. Taken together, these findings open new avenues for rational compound optimization and development of novel antifungal agents.

中文翻译：

---

具有抗真菌特性的吡咯啉酰胺和苯甲酰胺化学型的目标鉴定和作用机理

侵袭性真菌感染伴随着高达90％的高死亡率。目前，只有三种不同的化合物可用于临床，并且这些化合物通常具有较低的生物利用度，毒性和耐药性。这些问题强调了对新型抗真菌剂的迫切需求。在此，我们报告了具有抗真菌特性的化学用途的苯甲酰胺和吡啶甲酰胺支架的鉴定。纯化蛋白的化学基因组分析和生化分析确定了酿酒酵母中主要的磷脂酰肌醇/磷脂酰胆碱转移蛋白Sec14p，是这些化合物的唯一必需靶标。功能性染色体组筛选鉴定了位于Sec14p的脂质结合口袋中的赋予抗性的残基。Sec14p化合物复合物的X射线共晶体结构的确定证实了在该腔中的结合，并使赋予抗性的残基和观察到的构效关系合理化。综上所述，这些发现为合理的化合物优化和新型抗真菌剂的开发开辟了新途径。