Resistance of Haemonchus sp. to monepantel and reduced efficacy of a derquantel / abamectin combination confirmed in sheep in NSW, Australia

Sales, N.; Love, S. C. J.

doi:10.1016/j.vetpar.2016.08.016

Cited by 78 publications

(48 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Due to the rapid emergence of anthelmintic resistance, even to some recently commercialised compounds (Scott et al., 2013, Van den Brom et al., 2015, Sales and Love, 2016, Cintra et al., 2016), there is a need to identify, validate, optimise and develop novel chemical entities for the treatment of parasitic worms of humans and agricultural animals (Geary et al., 2015). …”

Section: Resultsmentioning

confidence: 99%

Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes

Preston

Jiao

Baell

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

View full text Add to dashboard Cite

The discovery and development of novel anthelmintic classes is essential to sustain the control of socioeconomically important parasitic worms of humans and animals. With the aim of offering novel, lead-like scaffolds for drug discovery, Compounds Australia released the ‘Open Scaffolds’ collection containing 33,999 compounds, with extensive information available on the physicochemical properties of these chemicals. In the present study, we screened 14,464 prioritised compounds from the ‘Open Scaffolds’ collection against the exsheathed third-stage larvae (xL3s) of Haemonchus contortus using recently developed whole-organism screening assays. We identified a hit compound, called SN00797439, which was shown to reproducibly reduce xL3 motility by ≥ 70%; this compound induced a characteristic, “coiled” xL3 phenotype (IC50 = 3.46–5.93 μM), inhibited motility of fourth-stage larvae (L4s; IC50 = 0.31–12.5 μM) and caused considerable cuticular damage to L4s in vitro. When tested on other parasitic nematodes in vitro, SN00797439 was shown to inhibit (IC50 = 3–50 μM) adults of Ancylostoma ceylanicum (hookworm) and first-stage larvae of Trichuris muris (whipworm) and eventually kill (>90%) these stages. Furthermore, this compound completely inhibited the motility of female and male adults of Brugia malayi (50–100 μM) as well as microfilariae of both B. malayi and Dirofilaria immitis (heartworm). Overall, these results show that SN00797439 acts against genetically (evolutionarily) distant parasitic nematodes i.e. H. contortus and A. ceylanicum [strongyloids] vs. B. malayi and D. immitis [filarioids] vs. T. muris [enoplid], and, thus, might offer a novel, lead-like scaffold for the development of a relatively broad-spectrum anthelmintic. Our future work will focus on assessing the activity of SN00797439 against other pathogens that cause neglected tropical diseases, optimising analogs with improved biological activities and characterising their targets.

show abstract

Section: Resultsmentioning

confidence: 99%

Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes

Preston

Jiao

Baell

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

View full text Add to dashboard Cite

show abstract

“…However, within several years of its release, resistance was reported in two species of worms infecting goats in New Zealand (Scott et al., 2013). More reports of resistance have followed since that time (Mederos et al., 2014, Van den Brom et al., 2015, Cintra et al., 2016, Sales and Love, 2016). …”

Section: Introductionmentioning

confidence: 99%

Mutations in the Hco-mptl-1 gene in a field-derived monepantel-resistant isolate of Haemonchus contortus

Bagnall

Ruffell

Raza

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

View full text Add to dashboard Cite

Resistance to the anthelmintic drug monepantel (Zolvix®) has emerged in parasitic worms infecting sheep and goats. The mechanism of resistance in these cases is unknown. The drug targets nicotinic acetylcholine receptors belonging to the nematode-specific DEG-3 subfamily. We examined the receptor gene, Hco-mptl-1, in a highly Zolvix®-resistant and a -susceptible isolate of the parasitic nematode Haemonchus contortus. cDNA coding for the full length receptor protein (Hco-MPTL-1) was present in all clones prepared from a pool of susceptible larvae (21/21 clones) and approximately 50% of those from the resistant isolate (17/33). On the other hand, the remaining clones from the resistant isolate showed various mutations that resulted in truncated predicted proteins, missing at least one transmembrane domain. The most common mutation (11/33 clones) resulted in the retention of intron 15, a premature stop codon, and a truncated protein. Sequencing of intron 15 genomic DNA showed very few SNPs in susceptible larvae and in 12/18 clones from resistant larvae, alongside the presence of at least 17 SNPs in the remaining resistant clones. The present study shows that the highly resistant isolate has a number of mutations in the drug target gene that would most-likely result in a non-functional receptor, thus rendering the larvae insensitive to the drug. The presence of many wild-type sequences in this highly-resistant population suggests that there was a significant presence of heterozygotes in the survivors of the field drench treatment from which the isolate was derived, and hence that at least some of the mutations may be dominant. Alternatively, their presence may be due to the additional influence of mutations at another locus contributing to the resistance phenotype. The presence of multiple separate mutations in the Hco-mptl-1 gene in this viable field-derived worm isolate may at least partly explain why resistance to Zolvix® has arisen rapidly in the field.

show abstract

“…Anthelmintic drug failure is an important economic and animal health problem, as anthelmintic resistance is widespread on farms, and populations and isolates resistant to all major classes of anthelmintics have been described [34-36]. Accordingly, significant research effort is focused on the development of novel anthelmintics [37] or vaccines [38] for parasite control.…”

Section: Introductionmentioning

confidence: 99%

A genome resequencing-based genetic map reveals the recombination landscape of an outbred parasitic nematode in the presence of polyploidy and polyandry

Doyle

Laing

Bartley

et al. 2017

Preprint

View full text Add to dashboard Cite

The parasitic nematode Haemonchus contortus is an economically and clinically important pathogen of small ruminants, and a model system for understanding the mechanisms and evolution of traits such as anthelmintic resistance. Anthelmintic resistance is widespread and is a major threat to the sustainability of livestock agriculture globally; however, little is known about the genome architecture and parameters such as recombination that will ultimately influence the rate at which resistance may evolve and spread. Here we performed a genetic cross between two divergent strains of H. contortus, and subsequently used whole-genome re-sequencing of a female worm and her brood to identify the distribution of genome-wide variation that characterises these strains. Using a novel bioinformatic approach to identify variants that segregate as expected in a pseudo-testcross, we characterised linkage groups and estimated genetic distances between markers to generate a chromosome-scale F1 genetic map composed of 1,618 SNPs. We exploited this map to reveal the recombination landscape, the first for any parasitic helminth species, demonstrating extensive variation in recombination rate within and between chromosomes. Analyses of these data also revealed the extent of polyandry, whereby at least eight males were found to have contributed to the genetic variation of the progeny analysed. Triploid offspring were also identified, which we hypothesise are the result of nondisjunction during female meiosis or polyspermy. These results expand our knowledge of the genetics of parasitic helminths and the unusual life-history of H. contortus, and will enable more precise characterisation of the evolution and inheritance of genetic traits such as anthelmintic resistance. This study also demonstrates the feasibility of whole-genome resequencing data to directly construct a genetic map in a single generation cross from a non-inbred non-model organism with a complex lifecycle.Author summaryRecombination is a key genetic process, responsible for the generation of novel genotypes and subsequent phenotypic variation as a result of crossing over between homologous chromosomes. Populations of strongylid nematodes, such as the gastrointestinal parasites that infect livestock and humans, are genetically very diverse, but little is known about patterns of recombination across the genome and how this may contribute to the genetics and evolution of these pathogens. In this study, we performed a genetic cross to quantify recombination in the barber’s pole worm, Haemonchus contortus, an important parasite of sheep and goats. The reproductive traits of this worm make standard genetic crosses challenging, but by generating whole-genome sequence data from a female worm and her offspring, we identified genetic variants that act as though they come from a single mating cross, allowing the use of standard statistical approaches to build a genetic map and explore the distribution and rates of recombination throughout the genome. A number of genetic signatures associated with H. contortus life history traits were revealed in this analysis: we extend our understanding of multiple paternity (polyandry) in this species, and provide evidence and explanation for sporadic increases in chromosome complements (polyploidy) among the progeny. The resulting genetic map will aid in population genomic studies in general and enhance ongoing efforts to understand the genetic basis of resistance to the drugs used to control these worms, as well as for related species that infect humans throughout the world.

show abstract

Resistance of Haemonchus sp. to monepantel and reduced efficacy of a derquantel / abamectin combination confirmed in sheep in NSW, Australia

Cited by 78 publications

References 13 publications

Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes

Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes

Mutations in the Hco-mptl-1 gene in a field-derived monepantel-resistant isolate of Haemonchus contortus

A genome resequencing-based genetic map reveals the recombination landscape of an outbred parasitic nematode in the presence of polyploidy and polyandry

Contact Info

Product

Resources

About