Mathew Mark D, Mathew Neal D, Miller Angela, Simpson Mike, Au Vinci, Garland Stephanie, Gestin Marie, Edgley Mark L, Flibotte Stephane, Balgi Aruna, Chiang Jennifer, Giaever Guri, Dean Pamela, Tung Audrey, Roberge Michel, Roskelley Calvin, Forge Tom, Nislow Corey, Moerman Donald
Department of Zoology and Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
PLoS Negl Trop Dis. 2016 Oct 18;10(10):e0005058. doi: 10.1371/journal.pntd.0005058. eCollection 2016 Oct.
The lack of new anthelmintic agents is of growing concern because it affects human health and our food supply, as both livestock and plants are affected. Two principal factors contribute to this problem. First, nematode resistance to anthelmintic drugs is increasing worldwide and second, many effective nematicides pose environmental hazards. In this paper we address this problem by deploying a high throughput screening platform for anthelmintic drug discovery using the nematode Caenorhabditis elegans as a surrogate for infectious nematodes. This method offers the possibility of identifying new anthelmintics in a cost-effective and timely manner.
METHODS/PRINCIPAL FINDINGS: Using our high throughput screening platform we have identified 14 new potential anthelmintics by screening more than 26,000 compounds from the Chembridge and Maybridge chemical libraries. Using phylogenetic profiling we identified a subset of the 14 compounds as potential anthelmintics based on the relative sensitivity of C. elegans when compared to yeast and mammalian cells in culture. We showed that a subset of these compounds might employ mechanisms distinct from currently used anthelmintics by testing diverse drug resistant strains of C. elegans. One of these newly identified compounds targets mitochondrial complex II, and we used structural analysis of the target to suggest how differential binding of this compound may account for its different effects in nematodes versus mammalian cells.
CONCLUSIONS/SIGNIFICANCE: The challenge of anthelmintic drug discovery is exacerbated by several factors; including, 1) the biochemical similarity between host and parasite genomes, 2) the geographic location of parasitic nematodes and 3) the rapid development of resistance. Accordingly, an approach that can screen large compound collections rapidly is required. C. elegans as a surrogate parasite offers the ability to screen compounds rapidly and, equally importantly, with specificity, thus reducing the potential toxicity of these compounds to the host and the environment. We believe this approach will help to replenish the pipeline of potential nematicides.
新型驱虫剂的匮乏日益令人担忧，因为它影响人类健康和我们的食物供应，牲畜和植物均受其影响。造成这一问题的主要有两个因素。其一，全球范围内线虫对驱虫药物的抗性在增加；其二，许多有效的杀线虫剂对环境有害。在本文中，我们通过部署一个高通量筛选平台来解决这一问题，该平台利用秀丽隐杆线虫作为感染性线虫的替代物来发现驱虫药物。这种方法提供了以具有成本效益且及时的方式鉴定新型驱虫剂的可能性。
方法/主要发现：利用我们的高通量筛选平台，通过筛选来自Chembridge和Maybridge化学文库的26000多种化合物，我们鉴定出了14种新的潜在驱虫剂。通过系统发育谱分析，基于秀丽隐杆线虫与培养中的酵母和哺乳动物细胞相比的相对敏感性，我们从这14种化合物中确定了一个子集作为潜在驱虫剂。通过测试秀丽隐杆线虫的多种耐药菌株，我们表明这些化合物中的一部分可能采用了与目前使用的驱虫剂不同的作用机制。这些新鉴定的化合物之一靶向线粒体复合物II，我们利用该靶点的结构分析来推测该化合物的差异结合如何解释其在秀丽隐杆线虫和哺乳动物细胞中的不同作用。
结论/意义：驱虫药物发现面临的挑战因几个因素而加剧，包括：1）宿主和寄生虫基因组之间的生化相似性；2）寄生线虫的地理位置；3）抗性的快速发展。因此，需要一种能够快速筛选大量化合物库的方法。秀丽隐杆线虫作为替代寄生虫，能够快速且同样重要的是特异性地筛选化合物，从而降低这些化合物对宿主和环境的潜在毒性。我们相信这种方法将有助于充实潜在杀线虫剂的储备。
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