An integrated computational and evidence-based approach identifies small molecule inhibitors detrimental to intestinal cells and tissue of parasitic nematodes

Authors: JASMER, DOUGLAS - Washington State University; ROSA, BRUCE - Washington State University; TYAGI, RAHUL - Washington State University; BULMAN, CHRISTINA - University Of California; BEERNSTEN, BRENDA - University Of Missouri; Urban, Joseph; SAKANARI, JUDY - University Of California; MITREVA, MAKEDONKA - Washington University School Of Medicine

Submitted to: PLOS Neglected Tropical Diseases
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/29/2019
Publication Date: 5/26/2020
Citation: Jasmer, D.P., Rosa, B.A., Tyagi, R., Bulman, C.A., Beernsten, B., Urban Jr, J.F., Sakanari, J., Mitreva, M. 2020. An integrated computational and evidence-based approach identifies small molecule inhibitors detrimental to intestinal cells and tissue of parasitic nematodes. PLOS Neglected Tropical Diseases. 14(5):e0007942. https://doi.org/10.1371/journal.pntd.0007942.
DOI: https://doi.org/10.1371/journal.pntd.0007942

Interpretive Summary: Parasitic nematodes (worms) that infect agricultural animals reduce production of meat, milk and fiber, and those that infect humans compromise health and well-being due to increased morbidity and reduced quality of life measures. The developmental and production costs, narrow efficacy against different classes of parasitic worms and increasing emergence of drug resistance to commercially available anti-worm drugs requires new therapeutic approaches and the definition of novel modes of action to ensure the availability of replacement drugs to control these infections. In this report, we applied molecular and multi-omics data analysis to this problem and demonstrated using advanced computational, functional genomic and laboratory screens the systematic and comprehensive identification of small molecule inhibitors that target the intestine of a wide variety of parasitic worms. The results demonstrate a broad control application of small molecules that damage different classes of worm parasites infecting both livestock and humans. The study also documents an array of detrimental effects on worm intestinal cells and tissues sometimes inducing irreparable damage that kills the worm under laboratory conditions. Some of these molecules have been previously used in either livestock or humans to target other diseases. Dual use drugs have the advantage of existing safety and efficacy testing to accelerate their application to live animals and humans. This information is important to those interested in novel drug development to control parasitic infection in livestock and humans in order to enhance their health and well-being in a cost effective and practical way.

Technical Abstract: Efforts to identify new drugs that can be used for therapeutic and preventive treatments against parasitic nematodes have gained increasing interest with expanding pathogen-omics databases and systematically organized drug databases from which new anthelmintic compounds might be identified. Here a novel approach focused on multi-omics databases, established in a pan-Nematoda context for a specific nematode organ system (the intestinal tract) were integrated with evidence-based filtering and drug database information. Exocytosis was identified as a high priority pathway and predicted inhibitors of exocytosis were tested using the large roundworm (Ascaris suum larval stages), a filarial worm (Brugia pahangi adult and L3), a whipworm (Trichuris muris adult), and the non-parasitic nematode Caenorhabditis elegans. Several distinct pathologic phenotypes were resolved related to molting, motility, or intestinal cell and tissue damage using conventional and novel histologic methods. Pathologic profiles characteristic for each inhibitor will guide future research to uncover mechanisms of the anthelmintic effects and improve on drug designs. This progress firmly validates the focus on intestinal cell biology as a useful resource to develop novel anthelmintic strategies.