Developing a Screen to Identify Microbial Natural Products with Potential Anthelmintic Activity Using Caenorhabditis Elegans

Abstract

Parasitic worm infections affect over a quarter of the human population, reducing quality of life and impacting global health. Helminth infections in farm animals are also highly prevalent and threaten the quality and quantity of agricultural resources. Despite the severity and frequency of helminthiases, few treatment options are available and rising levels of resistance to existing anthelmintics necessitates a more active drug discovery strategy. In the past, natural products have proven to be a rich source of clinically relevant therapeutics. There is currently no gold-standard protocol for anthelmintic compound screening, and efforts to look for anthelmintic chemicals from natural sources is also limited. To fill this gap, we developed a screening platform that uses Caenorhabditis elegans as a nematode model and optimized the assay conditions for natural product extract screening. Using outputs of motility and image analyses, we are able to identify extracts from environmental microbes that impact worm development. Further characterization confirmed the presence of nematocidal compounds tunicamycin and actinomycin D. We also identified and isolated xanthocillin as an inhibitor of worm growth. This has not been previously reported to have activity against nematodes but preliminary work presented here suggests that it works through heme sequestration. In the field, there has also been some interest in the nematode cuticle as a potential drug target. To assist in discovery efforts here, we also developed a protocol using a nanoluciferase-based reporter worm strain that responds to cuticle damage. The work presented here contributes to more focused anthelmintic drug discovery efforts. It provides valuable tools and insights that can be leveraged to assist in identifying compounds for the potential treatment of parasitic worm infections.