Haemonchus contortus

Tg, Geary

doi:10.1016/bs.apar.2016.02.013

Cited by 32 publications

(12 citation statements)

References 159 publications

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“…Numerous reviews have discussed the challenges associated with anthelmintic discovery and development (e.g., [ 1 , 10 , 11 ]). In an academic context, a key constraint or ‘bottleneck’ has been a lack of quantitative, automated platforms for the phenotypic screening of large numbers of compounds or small molecules for their effects on whole parasites [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Phenotypic Assay to Screen for Anthelmintic Activity on Haemonchus contortus

et al. 2021

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Parasitic worms cause very significant diseases in animals and humans worldwide, and their control is critical to enhance health, well-being and productivity. Due to widespread drug resistance in many parasitic worms of animals globally, there is a major, continuing demand for the discovery and development of anthelmintic drugs for use to control these worms. Here, we established a practical, cost-effective and semi-automated high throughput screening (HTS) assay, which relies on the measurement of motility of larvae of the barber’s pole worm (Haemonchus contortus) using infrared light-interference. Using this assay, we screened 80,500 small molecules and achieved a hit rate of 0.05%. We identified three small molecules that reproducibly inhibited larval motility and/or development (IC50 values of ~4 to 41 µM). Future work will critically assess the potential of selected hits as candidates for subsequent optimisation or repurposing against parasitic nematodes. This HTS assay has a major advantage over most previous assays in that it achieves a ≥ 10-times higher throughput (i.e., 10,000 compounds per week), and is thus suited to the screening of libraries of tens of thousands to hundreds of thousands of compounds for subsequent hit-to-lead optimisation or effective repurposing and development. The current assay should be adaptable to many socioeconomically important parasitic nematodes, including those that cause neglected tropical diseases (NTDs). This aspect is of relevance, given the goals of the World Health Organization (WHO) Roadmap for NTDs 2021–2030, to develop more effective drugs and drug combinations to improve patient outcomes and circumvent the ineffectiveness of some current anthelmintic drugs and possible drug resistance.

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Section: Introductionmentioning

confidence: 99%

High-Throughput Phenotypic Assay to Screen for Anthelmintic Activity on Haemonchus contortus

et al. 2021

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“…Resistance of H. contortus to almost all of the classes of anthelmintic drugs, including to multiple classes simultaneously, has been documented in many regions of the world [8–12], and can arise within a just a few years of introduction of a new drug class [13, 14]. Partly for these reasons, H. contortus has emerged as a model parasitic nematode to characterise anthelmintic resistance, as well as drug and vaccine discovery research as alternate means of control [15–17]. Its utility as a model is largely due to a greater amenability to experimentation than most parasitic nematodes; it is possible to establish and maintain isolates in vivo in the natural host, perform genetic crosses in vivo, and undertake in vitro culture for part of its life cycle, allowing drug assays and genetic manipulation such as RNAi to be performed [18].…”

Section: Introductionmentioning

confidence: 99%

Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus

et al. 2019

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BackgroundInfections with helminths cause an enormous disease burden in billions of animals and plants worldwide. Large scale use of anthelmintics has driven the evolution of resistance in a number of species that infect livestock and companion animals, and there are growing concerns regarding the reduced efficacy in some human-infective helminths. Understanding the mechanisms by which resistance evolves is the focus of increasing interest; robust genetic analysis of helminths is challenging, and although many candidate genes have been proposed, the genetic basis of resistance remains poorly resolved.ResultsHere, we present a genome-wide analysis of two genetic crosses between ivermectin resistant and sensitive isolates of the parasitic nematode Haemonchus contortus, an economically important gastrointestinal parasite of small ruminants and a model for anthelmintic research. Whole genome sequencing of parental populations, and key stages throughout the crosses, identified extensive genomic diversity that differentiates populations, but after backcrossing and selection, a single genomic quantitative trait locus (QTL) localised on chromosome V was revealed to be associated with ivermectin resistance. This QTL was common between the two geographically and genetically divergent resistant populations and did not include any leading candidate genes, suggestive of a previously uncharacterised mechanism and/or driver of resistance. Despite limited resolution due to low recombination in this region, population genetic analyses and novel evolutionary models supported strong selection at this QTL, driven by at least partial dominance of the resistant allele, and that large resistance-associated haplotype blocks were enriched in response to selection.ConclusionsWe have described the genetic architecture and mode of ivermectin selection, revealing a major genomic locus associated with ivermectin resistance, the most conclusive evidence to date in any parasitic nematode. This study highlights a novel genome-wide approach to the analysis of a genetic cross in non-model organisms with extreme genetic diversity, and the importance of a high-quality reference genome in interpreting the signals of selection so identified.Electronic supplementary materialThe online version of this article (10.1186/s12864-019-5592-6) contains supplementary material, which is available to authorized users.

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“…The discovery of new chemotherapeutics is imperative in the veterinary area, given the widespread problems associated with drug resistance, particularly in populations of parasitic roundworms (nematodes) of livestock animals (Geary, 2016; Kotze and Prichard, 2016). Even though new anthelmintics, such as monepantel (Kaminsky et al, 2008; Prichard and Geary, 2008) and derquantel (Little et al, 2010), were introduced relatively recently, resistance to these compounds have been reported (Kaminsky et al, 2011; Scott et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Selected α-pyrones from the plants Cryptocarya novoguineensis (Lauraceae) and Piper methysticum (Piperaceae) with activity against Haemonchus contortus in vitro

Herath

Preston

Jabbar

et al. 2019

International Journal for Parasitology: Drugs and Drug Resistan

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Due to the widespread occurrence and spread of anthelmintic resistance, there is a need to develop new drugs against resistant parasitic nematodes of livestock animals. The Nobel Prize-winning discovery and development of the anti-parasitic drugs avermectin and artemisinin has renewed the interest in exploring natural products as anthelmintics. In the present study, we screened 7500 plant extracts for in vitro-activity against the barber's pole worm, Haemonchus contortus, a highly significant pathogen of ruminants. The anthelmintic extracts from two plants, Cryptocarya novoguineensis and Piper methysticum, were fractionated by high-performance liquid chromatography (HPLC). Subsequently, compounds were purified from fractions with significant biological activity. Four α-pyrones, namely goniothalamin (GNT), dihydrokavain (DHK), desmethoxyyangonin (DMY) and yangonin (YGN), were purified from fractions from the two plants, GNT from C. novoguineensis, and DHK, DMY and YGN (= kavalactones) from P. methysticum. The three kavalactones induced a lethal, eviscerated (Evi) phenotype in treated exsheathed third-stage larvae (xL3s), and DMY and YGN had moderate potencies (IC50 values of 31.7 ± 0.23 μM and 23.7 ± 2.05 μM, respectively) at inhibiting the development of xL3s to fourth-stage larvae (L4s). Although GNT had limited potency (IC50 of 200–300 μM) at inhibiting L4 development, it was the only compound that reduced L4 motility (IC50 of 6.25–12.50 μM). The compounds purified from each plant affected H. contortus in an irreversible manner. These findings suggest that structure-activity relationship studies of α-pyrones should be pursued to assess their potential as anthelmintics.

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Haemonchus contortus

Cited by 32 publications

References 159 publications

High-Throughput Phenotypic Assay to Screen for Anthelmintic Activity on Haemonchus contortus

High-Throughput Phenotypic Assay to Screen for Anthelmintic Activity on Haemonchus contortus

Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus

Selected α-pyrones from the plants Cryptocarya novoguineensis (Lauraceae) and Piper methysticum (Piperaceae) with activity against Haemonchus contortus in vitro

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