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Inhibitors of Pathogen Intercellular Signals as Selective Anti-Infective Compounds
Long-term antibiotic use generates pan-resistant super pathogens. Anti-infective compounds that selectively disrupt virulence pathways without affecting cell viability may be used to efficiently combat infections caused by these pathogens. A candidate target pathway is quorum sensing (QS), which man...
Autores principales: | , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2007
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2323289/ https://www.ncbi.nlm.nih.gov/pubmed/17941706 http://dx.doi.org/10.1371/journal.ppat.0030126 |
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author | Lesic, Biliana Lépine, François Déziel, Eric Zhang, Jiangwen Zhang, Qunhao Padfield, Katie Castonguay, Marie-Hélène Milot, Sylvain Stachel, Scott Tzika, A. Aria Tompkins, Ronald G Rahme, Laurence G |
author_facet | Lesic, Biliana Lépine, François Déziel, Eric Zhang, Jiangwen Zhang, Qunhao Padfield, Katie Castonguay, Marie-Hélène Milot, Sylvain Stachel, Scott Tzika, A. Aria Tompkins, Ronald G Rahme, Laurence G |
author_sort | Lesic, Biliana |
collection | PubMed |
description | Long-term antibiotic use generates pan-resistant super pathogens. Anti-infective compounds that selectively disrupt virulence pathways without affecting cell viability may be used to efficiently combat infections caused by these pathogens. A candidate target pathway is quorum sensing (QS), which many bacterial pathogens use to coordinately regulate virulence determinants. The Pseudomonas aeruginosa MvfR-dependent QS regulatory pathway controls the expression of key virulence genes; and is activated via the extracellular signals 4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS), whose syntheses depend on anthranilic acid (AA), the primary precursor of 4-hydroxy-2-alkylquinolines (HAQs). Here, we identified halogenated AA analogs that specifically inhibited HAQ biosynthesis and disrupted MvfR-dependent gene expression. These compounds restricted P. aeruginosa systemic dissemination and mortality in mice, without perturbing bacterial viability, and inhibited osmoprotection, a widespread bacterial function. These compounds provide a starting point for the design and development of selective anti-infectives that restrict human P. aeruginosa pathogenesis, and possibly other clinically significant pathogens. |
format | Text |
id | pubmed-2323289 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-23232892008-04-18 Inhibitors of Pathogen Intercellular Signals as Selective Anti-Infective Compounds Lesic, Biliana Lépine, François Déziel, Eric Zhang, Jiangwen Zhang, Qunhao Padfield, Katie Castonguay, Marie-Hélène Milot, Sylvain Stachel, Scott Tzika, A. Aria Tompkins, Ronald G Rahme, Laurence G PLoS Pathog Research Article Long-term antibiotic use generates pan-resistant super pathogens. Anti-infective compounds that selectively disrupt virulence pathways without affecting cell viability may be used to efficiently combat infections caused by these pathogens. A candidate target pathway is quorum sensing (QS), which many bacterial pathogens use to coordinately regulate virulence determinants. The Pseudomonas aeruginosa MvfR-dependent QS regulatory pathway controls the expression of key virulence genes; and is activated via the extracellular signals 4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS), whose syntheses depend on anthranilic acid (AA), the primary precursor of 4-hydroxy-2-alkylquinolines (HAQs). Here, we identified halogenated AA analogs that specifically inhibited HAQ biosynthesis and disrupted MvfR-dependent gene expression. These compounds restricted P. aeruginosa systemic dissemination and mortality in mice, without perturbing bacterial viability, and inhibited osmoprotection, a widespread bacterial function. These compounds provide a starting point for the design and development of selective anti-infectives that restrict human P. aeruginosa pathogenesis, and possibly other clinically significant pathogens. Public Library of Science 2007-09 2007-09-14 /pmc/articles/PMC2323289/ /pubmed/17941706 http://dx.doi.org/10.1371/journal.ppat.0030126 Text en © 2007 Lesic et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Lesic, Biliana Lépine, François Déziel, Eric Zhang, Jiangwen Zhang, Qunhao Padfield, Katie Castonguay, Marie-Hélène Milot, Sylvain Stachel, Scott Tzika, A. Aria Tompkins, Ronald G Rahme, Laurence G Inhibitors of Pathogen Intercellular Signals as Selective Anti-Infective Compounds |
title | Inhibitors of Pathogen Intercellular Signals as Selective Anti-Infective Compounds |
title_full | Inhibitors of Pathogen Intercellular Signals as Selective Anti-Infective Compounds |
title_fullStr | Inhibitors of Pathogen Intercellular Signals as Selective Anti-Infective Compounds |
title_full_unstemmed | Inhibitors of Pathogen Intercellular Signals as Selective Anti-Infective Compounds |
title_short | Inhibitors of Pathogen Intercellular Signals as Selective Anti-Infective Compounds |
title_sort | inhibitors of pathogen intercellular signals as selective anti-infective compounds |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2323289/ https://www.ncbi.nlm.nih.gov/pubmed/17941706 http://dx.doi.org/10.1371/journal.ppat.0030126 |
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