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Broad-Spectrum Inhibitors for Conserved Unique Phosphoethanolamine Methyltransferases in Parasitic Nematodes Possess Anthelmintic Efficacy

In humans, nematode infections are prevalent in developing countries, causing long-term ill health, particularly in children. Worldwide, nematode infections are prevalent in livestock and pets, affecting productivity and health. Anthelmintic drugs are the primary means of controlling nematodes, but...

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Autores principales: Zhang, Xuejin, Sicalo Gianechini, Leonor, Li, Kun, Kaplan, Ray M., Witola, William H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10269165/
https://www.ncbi.nlm.nih.gov/pubmed/37212658
http://dx.doi.org/10.1128/aac.00008-23
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author Zhang, Xuejin
Sicalo Gianechini, Leonor
Li, Kun
Kaplan, Ray M.
Witola, William H.
author_facet Zhang, Xuejin
Sicalo Gianechini, Leonor
Li, Kun
Kaplan, Ray M.
Witola, William H.
author_sort Zhang, Xuejin
collection PubMed
description In humans, nematode infections are prevalent in developing countries, causing long-term ill health, particularly in children. Worldwide, nematode infections are prevalent in livestock and pets, affecting productivity and health. Anthelmintic drugs are the primary means of controlling nematodes, but there is now high prevalence of anthelmintic resistance, requiring urgent identification of new molecular targets for anthelmintics with novel mechanisms of action. Here, we identified orthologous genes for phosphoethanolamine methyltransferases (PMTs) in nematodes within the families Trichostrongylidae, Dictyocaulidae, Chabertiidae, Ancylostomatoidea, and Ascarididae. We characterized these putative PMTs and found that they possess bona fide PMT catalytic activities. By complementing a mutant yeast strain lacking the ability to synthesize phosphatidylcholine, the PMTs were validated to catalyze the biosynthesis of phosphatidylcholine. Using an in vitro phosphoethanolamine methyltransferase assay with PMTs as enzymes, we identified compounds with cross-inhibitory effects against the PMTs. Corroboratively, treatment of PMT-complemented yeast with the PMT inhibitors blocked growth of the yeast, underscoring the essential role of the PMTs in phosphatidylcholine synthesis. Fifteen of the inhibitors with the highest activity against complemented yeast were tested against Haemonchus contortus using larval development and motility assays. Among them, four were found to possess potent anthelmintic activity against both multiple drug-resistant and susceptible isolates of H. contortus, with IC(50) values (95% confidence interval) of 4.30 μM (2.15–8.28), 4.46 μM (3.22–6.16), 28.7 μM (17.3–49.5), and 0.65 μM (0.21–1.88). Taken together, we have validated a molecular target conserved in a broad range of nematodes and identified its inhibitors that possess potent in vitro anthelmintic activity.
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spelling pubmed-102691652023-06-16 Broad-Spectrum Inhibitors for Conserved Unique Phosphoethanolamine Methyltransferases in Parasitic Nematodes Possess Anthelmintic Efficacy Zhang, Xuejin Sicalo Gianechini, Leonor Li, Kun Kaplan, Ray M. Witola, William H. Antimicrob Agents Chemother Experimental Therapeutics In humans, nematode infections are prevalent in developing countries, causing long-term ill health, particularly in children. Worldwide, nematode infections are prevalent in livestock and pets, affecting productivity and health. Anthelmintic drugs are the primary means of controlling nematodes, but there is now high prevalence of anthelmintic resistance, requiring urgent identification of new molecular targets for anthelmintics with novel mechanisms of action. Here, we identified orthologous genes for phosphoethanolamine methyltransferases (PMTs) in nematodes within the families Trichostrongylidae, Dictyocaulidae, Chabertiidae, Ancylostomatoidea, and Ascarididae. We characterized these putative PMTs and found that they possess bona fide PMT catalytic activities. By complementing a mutant yeast strain lacking the ability to synthesize phosphatidylcholine, the PMTs were validated to catalyze the biosynthesis of phosphatidylcholine. Using an in vitro phosphoethanolamine methyltransferase assay with PMTs as enzymes, we identified compounds with cross-inhibitory effects against the PMTs. Corroboratively, treatment of PMT-complemented yeast with the PMT inhibitors blocked growth of the yeast, underscoring the essential role of the PMTs in phosphatidylcholine synthesis. Fifteen of the inhibitors with the highest activity against complemented yeast were tested against Haemonchus contortus using larval development and motility assays. Among them, four were found to possess potent anthelmintic activity against both multiple drug-resistant and susceptible isolates of H. contortus, with IC(50) values (95% confidence interval) of 4.30 μM (2.15–8.28), 4.46 μM (3.22–6.16), 28.7 μM (17.3–49.5), and 0.65 μM (0.21–1.88). Taken together, we have validated a molecular target conserved in a broad range of nematodes and identified its inhibitors that possess potent in vitro anthelmintic activity. American Society for Microbiology 2023-05-22 /pmc/articles/PMC10269165/ /pubmed/37212658 http://dx.doi.org/10.1128/aac.00008-23 Text en Copyright © 2023 Zhang et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Experimental Therapeutics
Zhang, Xuejin
Sicalo Gianechini, Leonor
Li, Kun
Kaplan, Ray M.
Witola, William H.
Broad-Spectrum Inhibitors for Conserved Unique Phosphoethanolamine Methyltransferases in Parasitic Nematodes Possess Anthelmintic Efficacy
title Broad-Spectrum Inhibitors for Conserved Unique Phosphoethanolamine Methyltransferases in Parasitic Nematodes Possess Anthelmintic Efficacy
title_full Broad-Spectrum Inhibitors for Conserved Unique Phosphoethanolamine Methyltransferases in Parasitic Nematodes Possess Anthelmintic Efficacy
title_fullStr Broad-Spectrum Inhibitors for Conserved Unique Phosphoethanolamine Methyltransferases in Parasitic Nematodes Possess Anthelmintic Efficacy
title_full_unstemmed Broad-Spectrum Inhibitors for Conserved Unique Phosphoethanolamine Methyltransferases in Parasitic Nematodes Possess Anthelmintic Efficacy
title_short Broad-Spectrum Inhibitors for Conserved Unique Phosphoethanolamine Methyltransferases in Parasitic Nematodes Possess Anthelmintic Efficacy
title_sort broad-spectrum inhibitors for conserved unique phosphoethanolamine methyltransferases in parasitic nematodes possess anthelmintic efficacy
topic Experimental Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10269165/
https://www.ncbi.nlm.nih.gov/pubmed/37212658
http://dx.doi.org/10.1128/aac.00008-23
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