Screening of the 'Pathogen Box' identifies an approved pesticide with major anthelmintic activity against the barber's pole worm. Issue 3 (December 2016)

• Record Type: Journal Article
• Authors: Preston, Sarah; Jiao, Yaqing; Jabbar, Abdul; McGee, Sean L.; Laleu, Benoît; Willis, Paul; Wells, Timothy N.C.; Gasser, Robin B.
• Is Part Of: International journal for parasitology. Volume 6:Issue 3(2016)
• Page Start: 329
• Page End: 334
• Publication Date: 2016-12
• Subjects: Haemonchus contortus -- Anthelmintic screening -- Pathogen Box -- Tolfenpyrad -- Mitochondrial respiratory chain; Parasitic diseases -- Chemotherapy -- Periodicals; Drug resistance -- Periodicals; 616.96061
• DOI: 10.1016/j.ijpddr.2016.07.004
• Languages: English
• ISSNs: 2211-3207

Abstract

Abstract: There is a substantial need to develop new medicines against parasitic diseases via public-private partnerships. Based on high throughput phenotypic screens of largely protozoal pathogens and bacteria, the Medicines for Malaria Venture (MMV) has recently assembled an open-access 'Pathogen Box' containing 400 well-curated chemical compounds. In the present study, we tested these compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm). In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility, growth and development of H. contortus . We also studied the effect of the 'hit' compound on mitochondrial function by measuring oxygen consumption. Among the 400 Pathogen Box compounds, we identified one chemical, called tolfenpyrad (compound identification code: MMV688934) that reproducibly inhibits xL3 motility as well as L4 motility, growth and development, with IC50 values ranging between 0.02 and 3 μM. An assessment of mitochondrial function showed that xL3s treated with tolfenpyrad consumed significantly less oxygen than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. Given that tolfenpyrad was developed as a pesticide and has already been tested for absorption, distribution, excretion, biotransformation, toxicity and metabolism, it shows considerable promise for hit-to-lead optimisation and/or repurposing for use against H. contortus and other parasitic nematodes. Future work should assess its activity against hookworms and other pathogens that cause neglected tropical diseases. Graphical abstract: Highlights: We screened compounds in the 'Pathogen Box' for activity against the parasitic nematode Haemonchus contortus . Tolfenpyrad, a pyrazole-5-carboxamide-based insecticide, has significant anthelmintic activity. Tolfenpyrad inhibits oxygen consumption in parasitic larvae of H. contortus .