Mapping resistance-associated anthelmintic interactions in the model nematode Caenorhabditis elegans.
Parasitic nematodes infect billions of people and are mainly controlled by anthelmintic mass drug administration (MDA). While there are growing efforts to better understand mechanisms of anthelmintic resistance in human and animal populations, it is unclear how resistance mechanisms that alter susce...
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ftdoajarticles:oai:doaj.org/article:8f24a89aea0f4af79252e45346c44054 2023-12-31T10:04:00+01:00 Mapping resistance-associated anthelmintic interactions in the model nematode Caenorhabditis elegans. Elena G Rehborg Nicolas J Wheeler Mostafa Zamanian 2023-10-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0011705 https://doaj.org/article/8f24a89aea0f4af79252e45346c44054 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0011705 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0011705 https://doaj.org/article/8f24a89aea0f4af79252e45346c44054 PLoS Neglected Tropical Diseases, Vol 17, Iss 10, p e0011705 (2023) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2023 ftdoajarticles https://doi.org/10.1371/journal.pntd.0011705 2023-12-03T01:41:39Z Parasitic nematodes infect billions of people and are mainly controlled by anthelmintic mass drug administration (MDA). While there are growing efforts to better understand mechanisms of anthelmintic resistance in human and animal populations, it is unclear how resistance mechanisms that alter susceptibility to one drug affect the interactions and efficacy of drugs used in combination. Mutations that alter drug permeability across primary nematode barriers have been identified as potential resistance mechanisms using the model nematode Caenorhabditis elegans. We leveraged high-throughput assays in this model system to measure altered anthelmintic susceptibility in response to genetic perturbations of potential cuticular, amphidial, and alimentary routes of drug entry. Mutations in genes associated with these tissue barriers differentially altered susceptibility to the major anthelmintic classes (macrocyclic lactones, benzimidazoles, and nicotinic acetylcholine receptor agonists) as measured by animal development. We investigated two-way anthelmintic interactions across C. elegans genetic backgrounds that confer resistance or hypersensitivity to one or more drugs. We observe that genetic perturbations that alter susceptibility to a single drug can shift the drug interaction landscape and lead to the appearance of novel synergistic and antagonistic interactions. This work establishes a framework for investigating combinatorial therapies in model nematodes that can potentially be translated to amenable parasite species. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles PLOS Neglected Tropical Diseases 17 10 e0011705 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Elena G Rehborg Nicolas J Wheeler Mostafa Zamanian Mapping resistance-associated anthelmintic interactions in the model nematode Caenorhabditis elegans. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Parasitic nematodes infect billions of people and are mainly controlled by anthelmintic mass drug administration (MDA). While there are growing efforts to better understand mechanisms of anthelmintic resistance in human and animal populations, it is unclear how resistance mechanisms that alter susceptibility to one drug affect the interactions and efficacy of drugs used in combination. Mutations that alter drug permeability across primary nematode barriers have been identified as potential resistance mechanisms using the model nematode Caenorhabditis elegans. We leveraged high-throughput assays in this model system to measure altered anthelmintic susceptibility in response to genetic perturbations of potential cuticular, amphidial, and alimentary routes of drug entry. Mutations in genes associated with these tissue barriers differentially altered susceptibility to the major anthelmintic classes (macrocyclic lactones, benzimidazoles, and nicotinic acetylcholine receptor agonists) as measured by animal development. We investigated two-way anthelmintic interactions across C. elegans genetic backgrounds that confer resistance or hypersensitivity to one or more drugs. We observe that genetic perturbations that alter susceptibility to a single drug can shift the drug interaction landscape and lead to the appearance of novel synergistic and antagonistic interactions. This work establishes a framework for investigating combinatorial therapies in model nematodes that can potentially be translated to amenable parasite species. |
format |
Article in Journal/Newspaper |
author |
Elena G Rehborg Nicolas J Wheeler Mostafa Zamanian |
author_facet |
Elena G Rehborg Nicolas J Wheeler Mostafa Zamanian |
author_sort |
Elena G Rehborg |
title |
Mapping resistance-associated anthelmintic interactions in the model nematode Caenorhabditis elegans. |
title_short |
Mapping resistance-associated anthelmintic interactions in the model nematode Caenorhabditis elegans. |
title_full |
Mapping resistance-associated anthelmintic interactions in the model nematode Caenorhabditis elegans. |
title_fullStr |
Mapping resistance-associated anthelmintic interactions in the model nematode Caenorhabditis elegans. |
title_full_unstemmed |
Mapping resistance-associated anthelmintic interactions in the model nematode Caenorhabditis elegans. |
title_sort |
mapping resistance-associated anthelmintic interactions in the model nematode caenorhabditis elegans. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2023 |
url |
https://doi.org/10.1371/journal.pntd.0011705 https://doaj.org/article/8f24a89aea0f4af79252e45346c44054 |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 17, Iss 10, p e0011705 (2023) |
op_relation |
https://doi.org/10.1371/journal.pntd.0011705 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0011705 https://doaj.org/article/8f24a89aea0f4af79252e45346c44054 |
op_doi |
https://doi.org/10.1371/journal.pntd.0011705 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
17 |
container_issue |
10 |
container_start_page |
e0011705 |
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1786828434905759744 |