Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity.
The lack of new anthelmintic agents is of growing concern because it affects human health and our food supply, as both livestock and plants are affected. Two principal factors contribute to this problem. First, nematode resistance to anthelmintic drugs is increasing worldwide and second, many effect...
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ftdoajarticles:oai:doaj.org/article:bf918819764c48fb8380f8fa310027ae 2023-05-15T15:14:19+02:00 Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity. Mark D Mathew Neal D Mathew Angela Miller Mike Simpson Vinci Au Stephanie Garland Marie Gestin Mark L Edgley Stephane Flibotte Aruna Balgi Jennifer Chiang Guri Giaever Pamela Dean Audrey Tung Michel Roberge Calvin Roskelley Tom Forge Corey Nislow Donald Moerman 2016-10-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0005058 https://doaj.org/article/bf918819764c48fb8380f8fa310027ae EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC5068747?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0005058 https://doaj.org/article/bf918819764c48fb8380f8fa310027ae PLoS Neglected Tropical Diseases, Vol 10, Iss 10, p e0005058 (2016) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2016 ftdoajarticles https://doi.org/10.1371/journal.pntd.0005058 2022-12-31T05:33:58Z The lack of new anthelmintic agents is of growing concern because it affects human health and our food supply, as both livestock and plants are affected. Two principal factors contribute to this problem. First, nematode resistance to anthelmintic drugs is increasing worldwide and second, many effective nematicides pose environmental hazards. In this paper we address this problem by deploying a high throughput screening platform for anthelmintic drug discovery using the nematode Caenorhabditis elegans as a surrogate for infectious nematodes. This method offers the possibility of identifying new anthelmintics in a cost-effective and timely manner.Using our high throughput screening platform we have identified 14 new potential anthelmintics by screening more than 26,000 compounds from the Chembridge and Maybridge chemical libraries. Using phylogenetic profiling we identified a subset of the 14 compounds as potential anthelmintics based on the relative sensitivity of C. elegans when compared to yeast and mammalian cells in culture. We showed that a subset of these compounds might employ mechanisms distinct from currently used anthelmintics by testing diverse drug resistant strains of C. elegans. One of these newly identified compounds targets mitochondrial complex II, and we used structural analysis of the target to suggest how differential binding of this compound may account for its different effects in nematodes versus mammalian cells.The challenge of anthelmintic drug discovery is exacerbated by several factors; including, 1) the biochemical similarity between host and parasite genomes, 2) the geographic location of parasitic nematodes and 3) the rapid development of resistance. Accordingly, an approach that can screen large compound collections rapidly is required. C. elegans as a surrogate parasite offers the ability to screen compounds rapidly and, equally importantly, with specificity, thus reducing the potential toxicity of these compounds to the host and the environment. We believe this approach will help ... Article in Journal/Newspaper Arctic Human health Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 10 10 e0005058 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
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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 Mark D Mathew Neal D Mathew Angela Miller Mike Simpson Vinci Au Stephanie Garland Marie Gestin Mark L Edgley Stephane Flibotte Aruna Balgi Jennifer Chiang Guri Giaever Pamela Dean Audrey Tung Michel Roberge Calvin Roskelley Tom Forge Corey Nislow Donald Moerman Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
The lack of new anthelmintic agents is of growing concern because it affects human health and our food supply, as both livestock and plants are affected. Two principal factors contribute to this problem. First, nematode resistance to anthelmintic drugs is increasing worldwide and second, many effective nematicides pose environmental hazards. In this paper we address this problem by deploying a high throughput screening platform for anthelmintic drug discovery using the nematode Caenorhabditis elegans as a surrogate for infectious nematodes. This method offers the possibility of identifying new anthelmintics in a cost-effective and timely manner.Using our high throughput screening platform we have identified 14 new potential anthelmintics by screening more than 26,000 compounds from the Chembridge and Maybridge chemical libraries. Using phylogenetic profiling we identified a subset of the 14 compounds as potential anthelmintics based on the relative sensitivity of C. elegans when compared to yeast and mammalian cells in culture. We showed that a subset of these compounds might employ mechanisms distinct from currently used anthelmintics by testing diverse drug resistant strains of C. elegans. One of these newly identified compounds targets mitochondrial complex II, and we used structural analysis of the target to suggest how differential binding of this compound may account for its different effects in nematodes versus mammalian cells.The challenge of anthelmintic drug discovery is exacerbated by several factors; including, 1) the biochemical similarity between host and parasite genomes, 2) the geographic location of parasitic nematodes and 3) the rapid development of resistance. Accordingly, an approach that can screen large compound collections rapidly is required. C. elegans as a surrogate parasite offers the ability to screen compounds rapidly and, equally importantly, with specificity, thus reducing the potential toxicity of these compounds to the host and the environment. We believe this approach will help ... |
format |
Article in Journal/Newspaper |
author |
Mark D Mathew Neal D Mathew Angela Miller Mike Simpson Vinci Au Stephanie Garland Marie Gestin Mark L Edgley Stephane Flibotte Aruna Balgi Jennifer Chiang Guri Giaever Pamela Dean Audrey Tung Michel Roberge Calvin Roskelley Tom Forge Corey Nislow Donald Moerman |
author_facet |
Mark D Mathew Neal D Mathew Angela Miller Mike Simpson Vinci Au Stephanie Garland Marie Gestin Mark L Edgley Stephane Flibotte Aruna Balgi Jennifer Chiang Guri Giaever Pamela Dean Audrey Tung Michel Roberge Calvin Roskelley Tom Forge Corey Nislow Donald Moerman |
author_sort |
Mark D Mathew |
title |
Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity. |
title_short |
Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity. |
title_full |
Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity. |
title_fullStr |
Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity. |
title_full_unstemmed |
Using C. elegans Forward and Reverse Genetics to Identify New Compounds with Anthelmintic Activity. |
title_sort |
using c. elegans forward and reverse genetics to identify new compounds with anthelmintic activity. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2016 |
url |
https://doi.org/10.1371/journal.pntd.0005058 https://doaj.org/article/bf918819764c48fb8380f8fa310027ae |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic Human health |
genre_facet |
Arctic Human health |
op_source |
PLoS Neglected Tropical Diseases, Vol 10, Iss 10, p e0005058 (2016) |
op_relation |
http://europepmc.org/articles/PMC5068747?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0005058 https://doaj.org/article/bf918819764c48fb8380f8fa310027ae |
op_doi |
https://doi.org/10.1371/journal.pntd.0005058 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
10 |
container_issue |
10 |
container_start_page |
e0005058 |
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1766344791762665472 |