Department of Chemistry, Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, Florida 32080, United States.
Loxo Oncology, Lilly, Louisville, Colorado 80027, United States.
J Nat Prod. 2023 Jul 28;86(7):1723-1735. doi: 10.1021/acs.jnatprod.3c00148. Epub 2023 Jul 6.
The saprotrophic filamentous fungus represents a chemically underexplored ascomycete with a high number of putative biosynthetic gene clusters in its genome. Here, we present new linear lipopeptides from nongenetic gene activation experiments using nutrient and salt variations. Metabolomics studies revealed four myropeptins, and structural analyses by NMR, HRMS, Marfey's analysis, and ECD assessment for their helical properties established their absolute configuration. A myropeptin biosynthetic gene cluster in the genome was identified. The myropeptins exhibit general nonspecific toxicity against all cancer cell lines in the NCI-60 panel, larval zebrafish with EC concentrations of 5-30 μM, and pathogenic bacteria and fungi (MICs of 4-32 μg/mL against multidrug-resistant and ). hemolysis, cell viability, and ionophore assays indicate that the myropeptins target mitochondrial and cellular membranes, inducing cell depolarization and cell death. The toxic activity is modulated by the length of the lipid side chain, which provides valuable insight into their structure-activity relationships.
腐生丝状真菌 是一种在化学上尚未得到充分探索的子囊菌，其基因组中有大量假定的生物合成基因簇。在这里，我们通过营养和盐度变化的非遗传基因激活实验，从该真菌中发现了四种新的线性脂肽。代谢组学研究揭示了四种 myropeptin，通过 NMR、高分辨质谱、Marfey 分析和 ECD 评估对其螺旋性质的结构分析确定了它们的绝对构型。在基因组中鉴定出一个 myropeptin 生物合成基因簇。Myropeptin 对 NCI-60 面板中的所有癌细胞系、EC 浓度为 5-30 μM 的幼期斑马鱼以及多药耐药性 和 的致病细菌和真菌均表现出一般的非特异性毒性（MIC 为 4-32 μg/mL）。溶血、细胞活力和离子载体测定表明，myropeptin 靶向线粒体和细胞膜，诱导细胞去极化和细胞死亡。毒性活性受脂质侧链长度的调节，这为它们的结构-活性关系提供了有价值的见解。
