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Identification of Antimotilins, Novel Inhibitors of Helicobacter pylori Flagellar Motility That Inhibit Stomach Colonization in a Mouse Model

New treatment options against the widespread cancerogenic gastric pathogen Helicobacter pylori are urgently needed. We describe a novel screening procedure for inhibitors of H. pylori flagellar biosynthesis. The assay is based on a flaA flagellin gene-luciferase reporter fusion in H. pylori and was...

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Autores principales: Suerbaum, Sebastian, Coombs, Nina, Patel, Lubna, Pscheniza, Dimitri, Rox, Katharina, Falk, Christine, Gruber, Achim D., Kershaw, Olivia, Chhatwal, Patrick, Brönstrup, Mark, Bilitewski, Ursula, Josenhans, Christine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8941896/
https://www.ncbi.nlm.nih.gov/pubmed/35227071
http://dx.doi.org/10.1128/mbio.03755-21
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author Suerbaum, Sebastian
Coombs, Nina
Patel, Lubna
Pscheniza, Dimitri
Rox, Katharina
Falk, Christine
Gruber, Achim D.
Kershaw, Olivia
Chhatwal, Patrick
Brönstrup, Mark
Bilitewski, Ursula
Josenhans, Christine
author_facet Suerbaum, Sebastian
Coombs, Nina
Patel, Lubna
Pscheniza, Dimitri
Rox, Katharina
Falk, Christine
Gruber, Achim D.
Kershaw, Olivia
Chhatwal, Patrick
Brönstrup, Mark
Bilitewski, Ursula
Josenhans, Christine
author_sort Suerbaum, Sebastian
collection PubMed
description New treatment options against the widespread cancerogenic gastric pathogen Helicobacter pylori are urgently needed. We describe a novel screening procedure for inhibitors of H. pylori flagellar biosynthesis. The assay is based on a flaA flagellin gene-luciferase reporter fusion in H. pylori and was amenable to multi-well screening formats with an excellent Z factor. We screened various compound libraries to identify virulence blockers (“antimotilins”) that inhibit H. pylori motility or the flagellar type III secretion apparatus. We identified compounds that either inhibit both motility and the bacterial viability, or the flagellar system only, without negatively affecting bacterial growth. Novel anti-virulence compounds which suppressed flagellar biosynthesis in H. pylori were active on pure H. pylori cultures in vitro and partially suppressed motility directly, reduced flagellin transcript and flagellin protein amounts. We performed a proof-of-principle treatment study in a mouse model of chronic H. pylori infection and demonstrated a significant effect on H. pylori colonization for one antimotilin termed Active2 even as a monotherapy. The diversity of the intestinal microbiota was not significantly affected by Active2. In conclusion, the novel antimotilins active against motility and flagellar assembly bear promise to complement commonly used antibiotic-based combination therapies for treating and eradicating H. pylori infections.
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spelling pubmed-89418962022-03-24 Identification of Antimotilins, Novel Inhibitors of Helicobacter pylori Flagellar Motility That Inhibit Stomach Colonization in a Mouse Model Suerbaum, Sebastian Coombs, Nina Patel, Lubna Pscheniza, Dimitri Rox, Katharina Falk, Christine Gruber, Achim D. Kershaw, Olivia Chhatwal, Patrick Brönstrup, Mark Bilitewski, Ursula Josenhans, Christine mBio Research Article New treatment options against the widespread cancerogenic gastric pathogen Helicobacter pylori are urgently needed. We describe a novel screening procedure for inhibitors of H. pylori flagellar biosynthesis. The assay is based on a flaA flagellin gene-luciferase reporter fusion in H. pylori and was amenable to multi-well screening formats with an excellent Z factor. We screened various compound libraries to identify virulence blockers (“antimotilins”) that inhibit H. pylori motility or the flagellar type III secretion apparatus. We identified compounds that either inhibit both motility and the bacterial viability, or the flagellar system only, without negatively affecting bacterial growth. Novel anti-virulence compounds which suppressed flagellar biosynthesis in H. pylori were active on pure H. pylori cultures in vitro and partially suppressed motility directly, reduced flagellin transcript and flagellin protein amounts. We performed a proof-of-principle treatment study in a mouse model of chronic H. pylori infection and demonstrated a significant effect on H. pylori colonization for one antimotilin termed Active2 even as a monotherapy. The diversity of the intestinal microbiota was not significantly affected by Active2. In conclusion, the novel antimotilins active against motility and flagellar assembly bear promise to complement commonly used antibiotic-based combination therapies for treating and eradicating H. pylori infections. American Society for Microbiology 2022-03-01 /pmc/articles/PMC8941896/ /pubmed/35227071 http://dx.doi.org/10.1128/mbio.03755-21 Text en Copyright © 2022 Suerbaum 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 Research Article
Suerbaum, Sebastian
Coombs, Nina
Patel, Lubna
Pscheniza, Dimitri
Rox, Katharina
Falk, Christine
Gruber, Achim D.
Kershaw, Olivia
Chhatwal, Patrick
Brönstrup, Mark
Bilitewski, Ursula
Josenhans, Christine
Identification of Antimotilins, Novel Inhibitors of Helicobacter pylori Flagellar Motility That Inhibit Stomach Colonization in a Mouse Model
title Identification of Antimotilins, Novel Inhibitors of Helicobacter pylori Flagellar Motility That Inhibit Stomach Colonization in a Mouse Model
title_full Identification of Antimotilins, Novel Inhibitors of Helicobacter pylori Flagellar Motility That Inhibit Stomach Colonization in a Mouse Model
title_fullStr Identification of Antimotilins, Novel Inhibitors of Helicobacter pylori Flagellar Motility That Inhibit Stomach Colonization in a Mouse Model
title_full_unstemmed Identification of Antimotilins, Novel Inhibitors of Helicobacter pylori Flagellar Motility That Inhibit Stomach Colonization in a Mouse Model
title_short Identification of Antimotilins, Novel Inhibitors of Helicobacter pylori Flagellar Motility That Inhibit Stomach Colonization in a Mouse Model
title_sort identification of antimotilins, novel inhibitors of helicobacter pylori flagellar motility that inhibit stomach colonization in a mouse model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8941896/
https://www.ncbi.nlm.nih.gov/pubmed/35227071
http://dx.doi.org/10.1128/mbio.03755-21
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