The novel nematicide wact-86 interacts with aldicarb to kill nematodes
The novel nematicide wact-86 interacts with aldicarb to kill nematodes
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DOI：
10.1371/journal.pntd.0005502
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发表时间：
2017-04-01
影响因子：
3.8
通讯作者：
Roy, Peter J.
中科院分区：
文献类型：
--
作者：
Burns, Andrew R.;Bagg, Rachel;Roy, Peter J.
寄生线虫对全世界人类和动物健康产生负面影响。由于不利的毒性，杀线虫剂退出市场限制了可用的治疗选择。原则上，将较低剂量的杀线虫剂与增强其活性的分子共同施用可以减轻不良毒性而不影响功效。在这里，我们筛选了与涕灭威相互作用的新小分子，涕灭威是一种针对植物寄生线虫的高效治疗方法，但其毒性阻碍了其实用性。从我们收集的 638 种蠕虫生物活性化合物中，我们鉴定出 20 种分子，它们与涕灭威产生积极的相互作用，从而杀死或抑制模型线虫秀丽隐杆线虫的生长。我们研究了涕灭威和一种新型杀线虫剂 wact-86 之间的相互作用机制。我们发现羧酸酯酶GES-1水解wact-86，并且这种相互作用表现为涕灭威通过GES-1抑制wact-86的代谢。这项工作展示了线虫作为寻找能够与工业杀线虫剂积极相互作用的新分子的平台的效用，并为前瞻性发现工作提供了概念验证。
Parasitic nematodes negatively impact human and animal health worldwide. The market withdrawal of nematicidal agents due to unfavourable toxicities has limited the available treatment options. In principle, co-administering nematicides at lower doses along with molecules that potentiate their activity could mitigate adverse toxicities without compromising efficacy. Here, we screened for new small molecules that interact with aldicarb, which is a highly effective treatment for plant-parasitic nematodes whose toxicity hampers its utility. From our collection of 638 worm-bioactive compounds, we identified 20 molecules that interact positively with aldicarb to either kill or arrest the growth of the model nematode Caenorhabditis elegans. We investigated the mechanism of interaction between aldicarb and one of these novel nematicides called wact-86. We found that the carboxylesterase enzyme GES-1 hydrolyzes wact-86, and that the interaction is manifested by aldicarb's inhibition of wact-86's metabolism by GES-1. This work demonstrates the utility of C. elegans as a platform to search for new molecules that can positively interact with industrial nematicides, and provides proof-of-concept for prospective discovery efforts.