Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.

Etiological agents of acute, persistent, or relapsing clinical infections are often refractory to antibiotics due to multidrug resistance and/or antibiotic tolerance. Pseudomonas aeruginosa is an opportunistic Gram-negative bacterial pathogen that causes recalcitrant and severe acute chronic and per...

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Autores principales:	Melissa Starkey, Francois Lepine, Damien Maura, Arunava Bandyopadhaya, Biljana Lesic, Jianxin He, Tomoe Kitao, Valeria Righi, Sylvain Milot, Aria Tzika, Laurence Rahme
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/9aa02961081547b7bbda3bdbbafe6365
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spelling	oai:doaj.org-article:9aa02961081547b7bbda3bdbbafe63652021-11-25T05:46:09ZIdentification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.1553-73661553-737410.1371/journal.ppat.1004321https://doaj.org/article/9aa02961081547b7bbda3bdbbafe63652014-08-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25144274/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Etiological agents of acute, persistent, or relapsing clinical infections are often refractory to antibiotics due to multidrug resistance and/or antibiotic tolerance. Pseudomonas aeruginosa is an opportunistic Gram-negative bacterial pathogen that causes recalcitrant and severe acute chronic and persistent human infections. Here, we target the MvfR-regulated P. aeruginosa quorum sensing (QS) virulence pathway to isolate robust molecules that specifically inhibit infection without affecting bacterial growth or viability to mitigate selective resistance. Using a whole-cell high-throughput screen (HTS) and structure-activity relationship (SAR) analysis, we identify compounds that block the synthesis of both pro-persistence and pro-acute MvfR-dependent signaling molecules. These compounds, which share a benzamide-benzimidazole backbone and are unrelated to previous MvfR-regulon inhibitors, bind the global virulence QS transcriptional regulator, MvfR (PqsR); inhibit the MvfR regulon in multi-drug resistant isolates; are active against P. aeruginosa acute and persistent murine infections; and do not perturb bacterial growth. In addition, they are the first compounds identified to reduce the formation of antibiotic-tolerant persister cells. As such, these molecules provide for the development of next-generation clinical therapeutics to more effectively treat refractory and deleterious bacterial-human infections.Melissa StarkeyFrancois LepineDamien MauraArunava BandyopadhayaBiljana LesicJianxin HeTomoe KitaoValeria RighiSylvain MilotAria TzikaLaurence RahmePublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 10, Iss 8, p e1004321 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Melissa Starkey Francois Lepine Damien Maura Arunava Bandyopadhaya Biljana Lesic Jianxin He Tomoe Kitao Valeria Righi Sylvain Milot Aria Tzika Laurence Rahme Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.
description	Etiological agents of acute, persistent, or relapsing clinical infections are often refractory to antibiotics due to multidrug resistance and/or antibiotic tolerance. Pseudomonas aeruginosa is an opportunistic Gram-negative bacterial pathogen that causes recalcitrant and severe acute chronic and persistent human infections. Here, we target the MvfR-regulated P. aeruginosa quorum sensing (QS) virulence pathway to isolate robust molecules that specifically inhibit infection without affecting bacterial growth or viability to mitigate selective resistance. Using a whole-cell high-throughput screen (HTS) and structure-activity relationship (SAR) analysis, we identify compounds that block the synthesis of both pro-persistence and pro-acute MvfR-dependent signaling molecules. These compounds, which share a benzamide-benzimidazole backbone and are unrelated to previous MvfR-regulon inhibitors, bind the global virulence QS transcriptional regulator, MvfR (PqsR); inhibit the MvfR regulon in multi-drug resistant isolates; are active against P. aeruginosa acute and persistent murine infections; and do not perturb bacterial growth. In addition, they are the first compounds identified to reduce the formation of antibiotic-tolerant persister cells. As such, these molecules provide for the development of next-generation clinical therapeutics to more effectively treat refractory and deleterious bacterial-human infections.
format	article
author	Melissa Starkey Francois Lepine Damien Maura Arunava Bandyopadhaya Biljana Lesic Jianxin He Tomoe Kitao Valeria Righi Sylvain Milot Aria Tzika Laurence Rahme
author_facet	Melissa Starkey Francois Lepine Damien Maura Arunava Bandyopadhaya Biljana Lesic Jianxin He Tomoe Kitao Valeria Righi Sylvain Milot Aria Tzika Laurence Rahme
author_sort	Melissa Starkey
title	Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.
title_short	Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.
title_full	Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.
title_fullStr	Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.
title_full_unstemmed	Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.
title_sort	identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/9aa02961081547b7bbda3bdbbafe6365
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Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity.

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