Screening of the ‘Pathogen Box’ identifies an approved pesticide with major anthelmintic activity against the barber's pole worm
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’ conta...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-12-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320716300525 |
| _version_ | 1818321384945745920 |
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| author | Sarah Preston Yaqing Jiao Abdul Jabbar Sean L. McGee Benoît Laleu Paul Willis Timothy N.C. Wells Robin B. Gasser |
| author_facet | Sarah Preston Yaqing Jiao Abdul Jabbar Sean L. McGee Benoît Laleu Paul Willis Timothy N.C. Wells Robin B. Gasser |
| author_sort | Sarah Preston |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T10:40:03Z |
| format | Article |
| id | doaj.art-db3a431160a7488cabe0d23839f5dadc |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-12-13T10:40:03Z |
| publishDate | 2016-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-db3a431160a7488cabe0d23839f5dadc2022-12-21T23:50:33ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072016-12-016332933410.1016/j.ijpddr.2016.07.004Screening of the ‘Pathogen Box’ identifies an approved pesticide with major anthelmintic activity against the barber's pole wormSarah Preston0Yaqing Jiao1Abdul Jabbar2Sean L. McGee3Benoît Laleu4Paul Willis5Timothy N.C. Wells6Robin B. Gasser7Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, 3010, AustraliaFaculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, 3010, AustraliaFaculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, 3010, AustraliaMetabolic Research Unit, Metabolic Reprogramming Laboratory, School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, Victoria, 3216, AustraliaMedicines for Malaria Venture (MMV), Route de Pré-Bois 20, CH-1215, Geneva, SwitzerlandMedicines for Malaria Venture (MMV), Route de Pré-Bois 20, CH-1215, Geneva, SwitzerlandMedicines for Malaria Venture (MMV), Route de Pré-Bois 20, CH-1215, Geneva, SwitzerlandFaculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, 3010, AustraliaThere 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.http://www.sciencedirect.com/science/article/pii/S2211320716300525Haemonchus contortusAnthelmintic screeningPathogen BoxTolfenpyradMitochondrial respiratory chain |
| spellingShingle | Sarah Preston Yaqing Jiao Abdul Jabbar Sean L. McGee Benoît Laleu Paul Willis Timothy N.C. Wells Robin B. Gasser Screening of the ‘Pathogen Box’ identifies an approved pesticide with major anthelmintic activity against the barber's pole worm International Journal for Parasitology: Drugs and Drug Resistance Haemonchus contortus Anthelmintic screening Pathogen Box Tolfenpyrad Mitochondrial respiratory chain |
| title | Screening of the ‘Pathogen Box’ identifies an approved pesticide with major anthelmintic activity against the barber's pole worm |
| title_full | Screening of the ‘Pathogen Box’ identifies an approved pesticide with major anthelmintic activity against the barber's pole worm |
| title_fullStr | Screening of the ‘Pathogen Box’ identifies an approved pesticide with major anthelmintic activity against the barber's pole worm |
| title_full_unstemmed | Screening of the ‘Pathogen Box’ identifies an approved pesticide with major anthelmintic activity against the barber's pole worm |
| title_short | Screening of the ‘Pathogen Box’ identifies an approved pesticide with major anthelmintic activity against the barber's pole worm |
| title_sort | screening of the pathogen box identifies an approved pesticide with major anthelmintic activity against the barber s pole worm |
| topic | Haemonchus contortus Anthelmintic screening Pathogen Box Tolfenpyrad Mitochondrial respiratory chain |
| url | http://www.sciencedirect.com/science/article/pii/S2211320716300525 |
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