生物
代谢组学
基因簇
生物化学
基因
溶血
斑马鱼
体外
EC50型
微生物学
生物信息学
免疫学
作者
Annika Jagels,Donovon A. Adpressa,Elizabeth N. Kaweesa,Mark McCauley,Benjamin Philmus,James A. Strother,Sandra Loesgen
标识
DOI:10.1021/acs.jnatprod.3c00148
摘要
The saprotrophic filamentous fungus Myrothecium inundatum 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 EC50 concentrations of 5-30 μM, and pathogenic bacteria and fungi (MICs of 4-32 μg/mL against multidrug-resistant S. aureus and C. auris). In vitro 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.
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