title: Ivermectin resistance in nematodes may be caused by alteration of P-glycoprotein homolog.
abstract: 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.
authors.affiliation: Institute of Parasitology, Macdonald Campus of McGill University, Ste-Anne-de-Bellevue, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Xu
authors.forename: M
authors.initials: M
authors.lastname: Molento
authors.forename: W
authors.initials: W
authors.lastname: Blackhall
authors.forename: P
authors.initials: P
authors.lastname: Ribeiro
authors.forename: R
authors.initials: R
authors.lastname: Beech
authors.forename: R
authors.initials: R
authors.lastname: Prichard
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000969:Antinematodal Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D015139:Blotting, Southern; D003001:Cloning, Molecular; D018076:DNA, Complementary; D018432:Drug Resistance, Multiple / Q000235:genetics; D005260:Female; D017238:Genes, Helminth; D005849:Gerbillinae; D006188:Haemonchiasis / Q000188:drug therapy; D006189:Haemonchus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006801:Humans; D007559:Ivermectin / Q000494:pharmacology*; D018942:Macrolides; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D000969:Antinematodal Agents; D018076:DNA, Complementary; D018942:Macrolides; D007559:Ivermectin; D014700:Verapamil; C027837:moxidectin