Interactions of benzimidazoles (BZ) with tubulin from BZ-sensitive and BZ-resistant isolates of Haemonchus contortus.
The binding of tritiated benzimidazoles (BZs)-albendazole, parbendazole, oxibendazole, mebendazole, oxfendazole and fenbendazole-to crude tubulin extracts from BZ-susceptible and -resistant Haemonchus contortus has been examined. For all BZs, the binding was substantially lower in the resistant isolate. The extent of this reduction was dependent on the structure of the BZ, with mebendazole demonstrating superior binding to the resistant isolate than the other BZs. Enrichment of the crude tubulin extract using polylysine-linked agarose demonstrated that for both isolates more than 85% of the observed binding was to protein eluted in the tubulin-containing fraction. Based on biochemical kinetics, the change in tubulin associated with resistance is reduced capacity in resistant tubulin to bind BZ with little or no reduction in the association constant of the BZ-tubulin complex. Comparative egg hatch assay demonstrated a similar structural specificity with the resistance factor of mebendazole observed to be lower than that of albendazole, parbendazole, oxibendazole and thiabendazole. The results of both studies support the hypothesis that BZ resistance is due to a change in tubulin and that this change is dependent on the structure of the BZ.
D015766:Albendazole; D000818:Animals; D000969:Antinematodal Agents / Q000378:metabolism*; D001562:Benzimidazoles / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004351:Drug Resistance; D005273:Fenbendazole / Q000378:metabolism; D006189:Haemonchus / Q000378:metabolism*; D008463:Mebendazole / Q000378:metabolism; D011485:Protein Binding; D012756:Sheep; D014251:Trichostrongyloidea / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism*
D000969:Antinematodal Agents; D001562:Benzimidazoles; D014404:Tubulin; C011321:oxibendazole; D005273:Fenbendazole; D008463:Mebendazole; D015766:Albendazole; C100292:parbendazole; C011030:oxfendazole