P-glycoprotein selection in strains of Haemonchus contortus resistant to benzimidazoles.
Anthelmintic resistance in parasitic nematodes of livestock is a chronic problem in many parts of the world. Benzimidazoles are effective, broad-spectrum anthelmintics that bind to and selectively depolymerise microtubules. Resistance to the benzimidazoles, however, developed quickly and is caused by genetic changes in genes encoding beta-tubulins, subunits of microtubules. In Haemonchus contortus, resistance to avermectins has been correlated with genetic changes at a gene encoding a P-glycoprotein, a cell membrane transport protein that has a very high affinity for ivermectin. The substrate specificity of P-glycoprotein is very broad, and resistance to benzimidazoles can be modulated by lectins specific for P-glycoprotein. We investigated the possibility that genetic changes in P-glycoprotein might be correlated with benzimidazole resistance in nematodes. An analysis of restriction fragment length polymorphisms of a P-glycoprotein gene from a sensitive and a cambendazole-selected strain of H. contortus, derived from the sensitive strain, showed a significant difference in allele frequencies between strains. The frequency of one allele in particular increased substantially. The same allele was also found at a high frequency in an independently derived thiabendazole-selected field isolate. We present genetic evidence of selection at a P-glycoprotein locus during selection for benzimidzole resistance in H. contortus.
Blackhall
William J
WJ
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Ste.-Anne-de-Bellevue, QC H9X 3V4, Canada. wblack@tiho-hannover.de
Prichard
Roger K
RK
Beech
Robin N
RN
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D018509:DNA, Helminth / Q000737:chemistry / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D005787:Gene Frequency; D017238:Genes, Helminth; D006188:Haemonchiasis / Q000188:drug therapy / Q000662:veterinary*; D006189:Haemonchus / Q000187:drug effects* / Q000235:genetics; D008297:Male; D021261:Parasitic Sensitivity Tests / Q000662:veterinary; D016133:Polymerase Chain Reaction / Q000379:methods / Q000662:veterinary; D012150:Polymorphism, Restriction Fragment Length; D012641:Selection, Genetic; D013045:Species Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000871:Anthelmintics; D001562:Benzimidazoles; D018509:DNA, Helminth; C031000:benzimidazole