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Screening of the 'pathogen box' identifies an approved pesticide with major anthelmintic activity against the barber's pole worm

Preston, Sarah, Jiao, Yaqing, Jabbar, Abdul, Mcgee, Sean, Laleu, Benoit, Willis, Paul, Wells, Timothy N.C. and Gasser, Robin B. 2016, 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, vol. 6, no. 3, pp. 329-334, doi: 10.1016/j.ijpddr.2016.07.004.

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Title Screening of the 'pathogen box' identifies an approved pesticide with major anthelmintic activity against the barber's pole worm
Author(s) Preston, Sarah
Jiao, Yaqing
Jabbar, Abdul
Mcgee, Sean
Laleu, Benoit
Willis, Paul
Wells, Timothy N.C.
Gasser, Robin B.
Journal name International journal for parasitology: drugs and drug resistance
Volume number 6
Issue number 3
Start page 329
End page 334
Total pages 6
Publisher Elsevier
Place of publication Amsterdam, The Netherlands
Publication date 2016-12
ISSN 2211-3207
Keyword(s) Anthelmintic screening
Haemonchus contortus
Mitochondrial respiratory chain
Pathogen Box
Tolfenpyrad
Science & Technology
Life Sciences & Biomedicine
Parasitology
Pharmacology & Pharmacy
CHAGAS-DISEASE
PYRAZOLE DERIVATIVES
HAEMONCHUS-CONTORTUS
COMPLEX I
NEMATODES
DESIGN
Summary 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.
Language eng
DOI 10.1016/j.ijpddr.2016.07.004
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 929999 Health not elsewhere classified
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, The Authors
Persistent URL http://hdl.handle.net/10536/DRO/DU:30085980

Document type: Journal Article
Collection: School of Medicine
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