Taki Aya C, Brkljača Robert, Wang Tao, Koehler Anson V, Ma Guangxu, Danne Jill, Ellis Sarah, Hofmann Andreas, Chang Bill C H, Jabbar Abdul, Urban Sylvia, Gasser Robin B
Department of Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC 3010, Australia.
School of Science (Applied Chemistry and Environmental Science), RMIT University, Melbourne, VIC 3001, Australia.
Pathogens. 2020 Jul 9;9(7):550. doi: 10.3390/pathogens9070550.
Eight secondary metabolites ( to ) were isolated from a marine sponge, a marine alga and three terrestrial plants collected in Australia and subsequently chemically characterised. Here, these natural product-derived compounds were screened for in vitro-anthelmintic activity against the larvae and adult stages of (barber's pole worm)-a highly pathogenic parasitic nematode of ruminants. Using an optimised, whole-organism screening system, compounds were tested on exsheathed third-stage larvae (xL3s) and fourth-stage larvae (L4s). Anthelmintic activity was initially evaluated on these stages based on the inhibition of motility, development and/or changes in morphology (phenotype). We identified two compounds, 6-undecylsalicylic acid () and 6-tridecylsalicylic acid () isolated from the marine brown alga, with inhibitory effects on xL3 and L4 motility and larval development, and the induction of a "skinny-straight" phenotype. Subsequent testing showed that these two compounds had an acute nematocidal effect (within 1-12 h) on adult males and females of . Ultrastructural analysis of adult worms treated with compound revealed significant damage to subcuticular musculature and associated tissues and cellular organelles including mitochondria. In conclusion, the present study has discovered two algal compounds possessing acute anthelmintic effects and with potential for hit-to-lead progression. Future work should focus on undertaking a structure-activity relationship study and on elucidating the mode(s) of action of optimised compounds.
从澳大利亚采集的一种海洋海绵、一种海洋藻类和三种陆生植物中分离出了八种次生代谢产物（至），随后对其进行了化学表征。在此，对这些天然产物衍生的化合物进行了体外驱虫活性筛选，以对抗捻转血矛线虫（一种反刍动物的高致病性寄生线虫）的幼虫和成虫阶段。使用优化的全生物体筛选系统，在脱鞘第三期幼虫（xL3s）和第四期幼虫（L4s）上测试化合物。最初基于对运动性、发育和/或形态（表型）变化的抑制作用，对这些阶段的驱虫活性进行评估。我们鉴定出两种化合物，即从海洋褐藻中分离出的6-十一烷基水杨酸（）和6-十三烷基水杨酸（），它们对xL3和L4的运动性以及幼虫发育具有抑制作用，并诱导出“瘦直”表型。后续测试表明，这两种化合物对捻转血矛线虫的成年雄性和雌性具有急性杀线虫作用（在1-12小时内）。用化合物处理的成年蠕虫的超微结构分析显示，皮下肌肉组织以及包括线粒体在内的相关组织和细胞器受到了严重损伤。总之，本研究发现了两种具有急性驱虫作用且具有从先导化合物优化发展潜力的藻类化合物。未来的工作应集中在进行构效关系研究以及阐明优化化合物的作用方式上。
