The transcription factor SKN-1 and detoxification gene ugt-22 alter albendazole efficacy in Caenorhabditis elegans

Parasitic nematodes infect over 1/4 th of the human population and are a major burden on livestock and crop production. Benzimidazole class anthelmintics are widely used to treat infections, but resistance is a widespread problem. Mutation of genes encoding the benzimidazole target β-tubulin is a well-established mechanism of resistance, but recent evidence suggests that metabolism of the drugs may also occur. Our objective was to investigate contributions of the detoxification-response transcription factor SKN-1 to anthelmintic drug resistance using C. elegans. We find that skn-1 mutations alter EC(50) of the common benzimidazole albendazole in motility assays by 1.5–1.7 fold. We also identify ugt-22 as a detoxification gene associated with SKN-1 that influences albendazole efficacy. Mutation and overexpression of ugt-22 alter albendazole EC(50) by 2.3–2.5-fold. The influence of a nematode UGT on albendazole efficacy is consistent with recent studies demonstrating glucose conjugation of benzimidazoles.