Parasitic nematode infections cause an enormous global burden to both humans and livestock. Resistance to the limited arsenal of anthelmintic drugs used to combat these infections is widespread, including benzimidazole (BZ) compounds. Previous studies using the free-living nematode Caenorhabditis elegans to model parasitic nematode resistance have shown that loss-of-function mutations in the beta-tubulin gene
ben-1 confer resistance to BZ drugs. However, the mechanism of resistance and the tissue-specific susceptibility are not well known in any nematode species. To identify in which tissue(s)
ben-1 function underlies BZ susceptibility, transgenic strains that express
ben-1 in different tissues, including hypodermis, muscles, neurons, intestine, and ubiquitous expression were generated. High-throughput fitness assays were performed to measure and compare the quantitative responses to BZ compounds among different transgenic lines. Significant BZ susceptibility was observed in animals expressing
ben-1 in neurons, comparable to expression using the
ben-1 promoter. This result suggests that
ben-1 function in neurons underlies susceptibility to BZ. Subsetting neuronal expression of
ben-1 based on the neurotransmitter system further restricted
ben-1 function in cholinergic neurons to cause BZ susceptibility. These results better inform our current understanding of the cellular mode of action of BZs and also suggest additional treatments that might potentiate the effects of BZs in neurons.