Ivermectin resistance in nematodes may be caused by alteration of P-glycoprotein homolog

Mol Biochem Parasitol. 1998 Mar 15;91(2):327-35. doi: 10.1016/s0166-6851(97)00215-6.


Resistance to ivermectin and related drugs is an increasing problem for parasite control. The mechanism of ivermectin resistance in nematode parasites is currently unknown. Some P-glycoproteins and multidrug resistance proteins have been found to act as membrane transporters which pump drugs from the cell. A disruption of the mdrla gene, which encodes a P-glycoprotein in mice, results in hypersensitivity to ivermectin. Genes encoding members of the P-glycoprotein family are known to exist in nematodes but the involvement of P-glycoprotein in nematode ivermectin-resistance has not been described. Our data suggest that a P-glycoprotein may play a role in ivermectin resistance in the sheep nematode parasite Haemonchus contortus. A full length P-glycoprotein cDNA from H. contortus has been cloned and sequenced. Analysis of the sequence showed 61-65% homology to other P-glycoprotein/multidrug resistant protein sequences, such as mice, human and Caenorhabditis elegans. Expression of P-glycoprotein mRNA was higher in ivermectin-selected than unselected strains of H. contortus. An alteration in the restriction pattern was also found for the genomic locus of P-glycoprotein derived from ivermectin-selected strains of H. contortus compared with unselected strains. P-glycoprotein gene structure and/or its transcription are altered in ivermectin-selected H. contortus. The multidrug resistance reversing agent, verapamil, increased the efficacy of ivermectin and moxidectin against a moxidectin-selected strain of this nematode in jirds (Meriones unguiculatus). These data indicate that a P-glycoprotein may be involved in resistance to ivermectin and other macrocyclic lactones in H. contortus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology
  • Amino Acid Sequence
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Antinematodal Agents / pharmacology*
  • Blotting, Northern
  • Blotting, Southern
  • Cloning, Molecular
  • DNA, Complementary
  • Drug Resistance, Multiple / genetics
  • Female
  • Genes, Helminth
  • Gerbillinae
  • Haemonchiasis / drug therapy
  • Haemonchus / drug effects*
  • Haemonchus / genetics
  • Haemonchus / growth & development
  • Humans
  • Ivermectin / pharmacology*
  • Macrolides
  • Molecular Sequence Data
  • Sequence Alignment
  • Verapamil / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-Bacterial Agents
  • Antinematodal Agents
  • DNA, Complementary
  • Macrolides
  • Ivermectin
  • Verapamil
  • moxidectin

Associated data

  • GENBANK/AF003908