title: Screening of the 'Pathogen Box' identifies an approved pesticide with major anthelmintic activity against the barber's pole worm.
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 IC50values 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.
authors.affiliation: Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, 3010, Australia. Electronic address: sarah.preston@unimelb.edu.au.
authors.forename: Sarah
authors.initials: S
authors.lastname: Preston
authors.affiliation: Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, 3010, Australia. Electronic address: yaqingj@student.unimelb.edu.au.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, 3010, Australia. Electronic address: jabbara@unimelb.edu.au.
authors.forename: Abdul
authors.initials: A
authors.lastname: Jabbar
authors.affiliation: Metabolic Research Unit, Metabolic Reprogramming Laboratory, School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, Victoria, 3216, Australia. Electronic address: sean.mcgee@deakin.edu.au.
authors.forename: Sean L
authors.initials: SL
authors.lastname: McGee
authors.affiliation: Medicines for Malaria Venture (MMV), Route de Pré-Bois 20, CH-1215, Geneva, Switzerland. Electronic address: laleub@mmv.org.
authors.forename: Benoît
authors.initials: B
authors.lastname: Laleu
authors.affiliation: Medicines for Malaria Venture (MMV), Route de Pré-Bois 20, CH-1215, Geneva, Switzerland. Electronic address: willisp@mmv.org.
authors.forename: Paul
authors.initials: P
authors.lastname: Willis
authors.affiliation: Medicines for Malaria Venture (MMV), Route de Pré-Bois 20, CH-1215, Geneva, Switzerland. Electronic address: wellst@mmv.org.
authors.forename: Timothy N C
authors.initials: TNC
authors.lastname: Wells
authors.affiliation: Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, 3010, Australia. Electronic address: robinbg@unimelb.edu.au.
authors.forename: Robin B
authors.initials: RB
authors.lastname: Gasser
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D001681:Biological Assay; D004353:Drug Evaluation, Preclinical; D006189:Haemonchus / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D020128:Inhibitory Concentration 50; D008124:Locomotion / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*
chemical_list: D000871:Anthelmintics; D011720:Pyrazoles; C556693:tolfenpyrad
keywords: Anthelmintic screening; Haemonchus contortus; Mitochondrial respiratory chain; Pathogen Box; Tolfenpyrad