Abstract
AbstractBenzimidazole (BZ) anthelmintics are among the most important treatments for parasitic nematode infections in the developing world. Widespread BZ resistance in veterinary parasites and emerging resistance in human parasites raise major concerns for the continued use of BZs. Knowledge of the mechanisms of resistance is necessary to make informed treatment decisions and circumvent resistance. Benzimidazole resistance has traditionally been associated with mutations and natural variants in theC. elegansbeta-tubulin geneben-1and orthologs in parasitic species. However, variants inben-1alone do not explain the differences in BZ responses across parasite populations. Here, we examine the roles of fiveC. elegansbeta-tubulin genes (tbb-1,mec-7,tbb-4,ben-1, andtbb-6) to identify the role each gene plays in BZ response. We generatedC. elegansstrains with a loss of each beta-tubulin gene, as well as strains with a loss oftbb-1,mec-7,tbb-4, ortbb-6in a genetic background that also lacksben-1to test beta-tubulin redundancy in BZ response. We found that only the individual loss ofben-1conferred a substantial level of BZ resistance, although the loss oftbb-1was found to confer a small benefit in the presence of albendazole (ABZ). The loss ofben-1was found to confer an almost complete rescue of animal development in the presence of 30 µM ABZ, likely explaining why no additive effects caused by the loss of a second beta-tubulin were observed. We demonstrate thatben-1is the only beta-tubulin gene inC. eleganswhere loss confers substantial BZ resistance.Highlights-Loss ofben-1provides almost complete rescue of development in albendazole (ABZ)-Loss of different beta-tubulin genes does not confer ABZ resistance-Loss ofben-1and a second beta-tubulin does not enhance theben-1level of ABZ resistance
Publisher
Cold Spring Harbor Laboratory