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bioRxiv · 10.1101/2022.07.21.500991

Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin

Gibson, S. B.·Ness-Cohn, E.·Andersen, E. C.
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Abstract

Parasitic nematode infections cause an enormous global burden to both human and livestock populations. Resistance to the limited arsenal of anthelmintic drugs used to combat these infections is widespread, including resistance to benzimidazole (BZ) compounds commonly found in livestock parasites. 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 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 BZ and also suggest additional treatments that might potentiate the effects of BZs. HighlightsO_LIExpressing wild-type ben-1 only in neurons restores susceptibility to benzimidazoles C_LIO_LIExpression of ben-1 in cholinergic neurons restores susceptibility to benzimidazoles C_LIO_LIGABAergic neurons might also play a role in benzimidazole sensitivity C_LIO_LIBroad implications for molecular mechanisms of benzimidazole mode of action C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/500991v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@161cbb7org.highwire.dtl.DTLVardef@18578cforg.highwire.dtl.DTLVardef@1be80aaorg.highwire.dtl.DTLVardef@1f15236_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Gibson, S. B., Ness-Cohn, E., Andersen, E. C.. 2022-07-22. Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin. https://doi.org/10.1101/2022.07.21.500991

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