Dataset Information

Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus.

ABSTRACT:

Background

In this study, we tested five series of pyrazole-5-carboxamide compounds (n?=?55) for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm), one of the most pathogenic parasites of ruminants.

Methods

In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus.

Results

Amongst the 55 compounds, we identified two compounds (designated a-15 and a-17) that reproducibly inhibit xL3 motility as well as L4 motility and development, with IC₅₀ values ranging between ~3.4 and 55.6 ?M. We studied the effect of these two 'hit' compounds on mitochondrial function by measuring oxygen consumption. This assessment showed that xL3s exposed to each of these compounds consumed significantly less oxygen and had less mitochondrial activity than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods.

Conclusions

The present findings provide a sound basis for future work, aimed at identifying the targets of compounds a-15 and a-17 and establishing the modes of action of these chemicals in H. contortus.

SUBMITTER: Jiao Y

PROVIDER: S-EPMC5452367 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus.

Jiao Yaqing Y Preston Sarah S Song Hongjian H Jabbar Abdul A Liu Yuxiu Y Baell Jonathan J Hofmann Andreas A Hutchinson Dana D Wang Tao T Koehler Anson V AV Fisher Gillian M GM Andrews Katherine T KT Laleu Benoît B Palmer Michael J MJ Burrows Jeremy N JN Wells Timothy N C TNC Wang Qingmin Q Gasser Robin B RB

Parasites & vectors 20170531 1

<h4>Background</h4>In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm), one of the most pathogenic parasites of ruminants.<h4>Methods</h4>In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus.<h4>Results</h4>Amongst the 55 compounds, we ...[more]

PMID: 28569174

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Project description:BackgroundParasitic nematodes can cause substantial clinical and subclinical problems in alpacas and anthelmintics are regularly used to control parasitic nematodes in alpacas. Although anthelmintic resistance has been reported in ruminants worldwide, very little is known about anthelmintic resistance in alpacas. The present study was carried out to confirm a suspected case of anthelmintic resistance in Haemonchus contortus in alpacas in Australia.MethodsPost mortem examination of an alpaca was conducted to determine the cause of its death. To confirm a suspected case of macrocyclic lactone (ML) resistance in H. contortus in alpacas, a faecal egg count reduction test (FECRT) was performed using closantel (7.5 mg/kg) and ivermectin (0.2 mg/kg). Nematode species were identified by morphological and molecular methods.ResultsPost mortem examination of a 1-year-old female alpaca that had died following a brief period of lethargy, anorexia and recumbency revealed severe anaemia, hypoproteinaemia and gastric parasitism by adult Haemonchus contortus, despite recent abamectin (0.2 mg/kg) treatment. Based on these findings and the exclusive use of MLs in the herd over the preceding six years, ML resistance in parasitic nematodes of alpacas on this farm was suspected. FECRT revealed that the efficacy of closantel was 99% (95% CI 93-100), whereas that of ivermectin was 35% (95% CI 0-78), indicating that the treatment failure was likely due to the presence of ML-resistant nematodes. Larval culture of faecal samples collected following ivermectin treatment consisted of 99% H. contortus and 1% Cooperia oncophora, a result confirmed using a PCR assay.ConclusionsThis study provides the first evidence of ML resistance in H. contortus in alpacas in Australia. Based on the extent of anthelmintic resistance in sheep gastrointestinal nematodes in Australia, veterinarians and alpaca owners should be encouraged to implement integrated parasite management strategies to improve nematode control in alpacas.

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Dataset Information

Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus.

Background

Methods

Results

Conclusions

Publications

Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus.

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