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Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin
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 el...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9771835/ https://www.ncbi.nlm.nih.gov/pubmed/36332489 http://dx.doi.org/10.1016/j.ijpddr.2022.10.004 |
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author | Gibson, Sophia B. Ness-Cohn, Elan Andersen, Erik C. |
author_facet | Gibson, Sophia B. Ness-Cohn, Elan Andersen, Erik C. |
author_sort | Gibson, Sophia B. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9771835 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-97718352022-12-23 Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin Gibson, Sophia B. Ness-Cohn, Elan Andersen, Erik C. Int J Parasitol Drugs Drug Resist Regular article 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. Elsevier 2022-10-29 /pmc/articles/PMC9771835/ /pubmed/36332489 http://dx.doi.org/10.1016/j.ijpddr.2022.10.004 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Regular article Gibson, Sophia B. Ness-Cohn, Elan Andersen, Erik C. Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin |
title | Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin |
title_full | Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin |
title_fullStr | Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin |
title_full_unstemmed | Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin |
title_short | Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin |
title_sort | benzimidazoles cause lethality by inhibiting the function of caenorhabditis elegans neuronal beta-tubulin |
topic | Regular article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9771835/ https://www.ncbi.nlm.nih.gov/pubmed/36332489 http://dx.doi.org/10.1016/j.ijpddr.2022.10.004 |
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