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Macrocyclic lactones and their relationship to the SNPs related to benzimidazole resistance

Shoaib Ashraf1, Thangadurai Mani1, Robin Beech1

  • 1Institute of Parasitology, McGill University-Macdonald Campus, Sainte-Anne-de-Bellevue, Quebec H9X 3V9, Canada.

Molecular and Biochemical Parasitology
|August 9, 2015
PubMed

Insights

Single nucleotide polymorphisms (SNPs) in Haemonchus contortus do not affect ivermectin (IVM) binding or tubulin polymerization. However, differences in IVM and moxidectin (MOX) binding were observed between parasitic and mammalian tubulin.

Area of Science:

  • Veterinary Parasitology
  • Molecular Biology
  • Drug Resistance

Background:

  • Haemonchus contortus is a globally significant ruminant parasite, notorious for causing animal deaths and rapid anthelmintic resistance.
  • Ivermectin (IVM) and moxidectin (MOX), macrocyclic lactones, are key treatments, but resistance is a growing concern.
  • Genetic variations, specifically single nucleotide polymorphisms (SNPs) in the β-tubulin isotype 1 gene, have been linked to IVM resistance in H. contortus.

Purpose of the Study:

  • To investigate the impact of specific H. contortus SNPs (F167Y and F200Y) on β-tubulin polymerization and ivermectin binding.
  • To compare the effects of ivermectin and moxidectin on tubulin polymerization.
  • To elucidate the molecular interactions of these anthelmintics with both parasitic and mammalian tubulin.

Main Methods:

  • In vitro tubulin polymerization assays were performed using wild-type and mutant (F167Y, F200Y) β-tubulin from H. contortus.
  • Direct binding assays were conducted to assess ivermectin interaction with mutant and wild-type tubulin.
  • Molecular modeling (docking) was employed to visualize the binding of ivermectin and moxidectin to tubulin.

Main Results:

  • The studied SNPs (F167Y and F200Y) did not alter tubulin polymerization or reduce ivermectin binding affinity in H. contortus.
  • Differential polymerization effects were observed: IVM showed greater polymerization with H. contortus tubulin compared to MOX, while the reverse was true for mammalian tubulin.
  • Molecular modeling indicated that both IVM and MOX bind to the taxane pocket of tubulin, with stronger binding observed for mammalian tubulin than parasitic tubulin.

Conclusions:

  • The investigated SNPs in H. contortus β-tubulin are unlikely to be the primary mechanism driving ivermectin resistance through altered tubulin dynamics or drug binding.
  • Distinct binding interactions between ivermectin and moxidectin with parasitic versus mammalian tubulin may contribute to species-specific efficacy and resistance patterns.
  • Further research into the molecular basis of anthelmintic resistance in H. contortus is warranted.
Keywords:
IvermectinMoxidectinSingle nucleotide polymorphismTubulin

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