QseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens

ABSTRACT Invasive pathogens interface with the host and its resident microbiota through interkingdom signaling. The bacterial receptor QseC, which is a membrane-bound histidine sensor kinase, responds to the host stress hormones epinephrine and norepinephrine and the bacterial signal AI-3, integrati...

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Autores principales:	Meredith M. Curtis, Regan Russell, Cristiano G. Moreira, Adeniyi M. Adebesin, Changguang Wang, Noelle S. Williams, Ron Taussig, Don Stewart, Philippe Zimmern, Biao Lu, Ravi N. Prasad, Chen Zhu, David A. Rasko, Jason F. Huntley, John R. Falck, Vanessa Sperandio
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1061d94eb6464cb9a1f40f41a4252c50
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spelling	oai:doaj.org-article:1061d94eb6464cb9a1f40f41a4252c502021-11-15T15:47:04ZQseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens10.1128/mBio.02165-142150-7511https://doaj.org/article/1061d94eb6464cb9a1f40f41a4252c502014-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02165-14https://doaj.org/toc/2150-7511ABSTRACT Invasive pathogens interface with the host and its resident microbiota through interkingdom signaling. The bacterial receptor QseC, which is a membrane-bound histidine sensor kinase, responds to the host stress hormones epinephrine and norepinephrine and the bacterial signal AI-3, integrating interkingdom signaling at the biochemical level. Importantly, the QseC signaling cascade is exploited by many bacterial pathogens to promote virulence. Here, we translated this basic science information into development of a potent small molecule inhibitor of QseC, LED209. Extensive structure activity relationship (SAR) studies revealed that LED209 is a potent prodrug that is highly selective for QseC. Its warhead allosterically modifies lysines in QseC, impairing its function and preventing the activation of the virulence program of several Gram-negative pathogens both in vitro and during murine infection. LED209 does not interfere with pathogen growth, possibly leading to a milder evolutionary pressure toward drug resistance. LED209 has desirable pharmacokinetics and does not present toxicity in vitro and in rodents. This is a unique antivirulence approach, with a proven broad-spectrum activity against multiple Gram-negative pathogens that cause mammalian infections. IMPORTANCE There is an imminent need for development of novel treatments for infectious diseases, given that one of the biggest challenges to medicine in the foreseeable future is the emergence of microbial antibiotic resistance. Here, we devised a broad-spectrum antivirulence approach targeting a conserved histidine kinase, QseC, in several Gram-negative pathogens that promotes their virulence expression. The LED209 QseC inhibitor has a unique mode of action by acting as a prodrug scaffold to deliver a warhead that allosterically modifies QseC, impeding virulence in several Gram-negative pathogens.Meredith M. CurtisRegan RussellCristiano G. MoreiraAdeniyi M. AdebesinChangguang WangNoelle S. WilliamsRon TaussigDon StewartPhilippe ZimmernBiao LuRavi N. PrasadChen ZhuDavid A. RaskoJason F. HuntleyJohn R. FalckVanessa SperandioAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 6 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Meredith M. Curtis Regan Russell Cristiano G. Moreira Adeniyi M. Adebesin Changguang Wang Noelle S. Williams Ron Taussig Don Stewart Philippe Zimmern Biao Lu Ravi N. Prasad Chen Zhu David A. Rasko Jason F. Huntley John R. Falck Vanessa Sperandio QseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens
description	ABSTRACT Invasive pathogens interface with the host and its resident microbiota through interkingdom signaling. The bacterial receptor QseC, which is a membrane-bound histidine sensor kinase, responds to the host stress hormones epinephrine and norepinephrine and the bacterial signal AI-3, integrating interkingdom signaling at the biochemical level. Importantly, the QseC signaling cascade is exploited by many bacterial pathogens to promote virulence. Here, we translated this basic science information into development of a potent small molecule inhibitor of QseC, LED209. Extensive structure activity relationship (SAR) studies revealed that LED209 is a potent prodrug that is highly selective for QseC. Its warhead allosterically modifies lysines in QseC, impairing its function and preventing the activation of the virulence program of several Gram-negative pathogens both in vitro and during murine infection. LED209 does not interfere with pathogen growth, possibly leading to a milder evolutionary pressure toward drug resistance. LED209 has desirable pharmacokinetics and does not present toxicity in vitro and in rodents. This is a unique antivirulence approach, with a proven broad-spectrum activity against multiple Gram-negative pathogens that cause mammalian infections. IMPORTANCE There is an imminent need for development of novel treatments for infectious diseases, given that one of the biggest challenges to medicine in the foreseeable future is the emergence of microbial antibiotic resistance. Here, we devised a broad-spectrum antivirulence approach targeting a conserved histidine kinase, QseC, in several Gram-negative pathogens that promotes their virulence expression. The LED209 QseC inhibitor has a unique mode of action by acting as a prodrug scaffold to deliver a warhead that allosterically modifies QseC, impeding virulence in several Gram-negative pathogens.
format	article
author	Meredith M. Curtis Regan Russell Cristiano G. Moreira Adeniyi M. Adebesin Changguang Wang Noelle S. Williams Ron Taussig Don Stewart Philippe Zimmern Biao Lu Ravi N. Prasad Chen Zhu David A. Rasko Jason F. Huntley John R. Falck Vanessa Sperandio
author_facet	Meredith M. Curtis Regan Russell Cristiano G. Moreira Adeniyi M. Adebesin Changguang Wang Noelle S. Williams Ron Taussig Don Stewart Philippe Zimmern Biao Lu Ravi N. Prasad Chen Zhu David A. Rasko Jason F. Huntley John R. Falck Vanessa Sperandio
author_sort	Meredith M. Curtis
title	QseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens
title_short	QseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens
title_full	QseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens
title_fullStr	QseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens
title_full_unstemmed	QseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens
title_sort	qsec inhibitors as an antivirulence approach for gram-negative pathogens
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/1061d94eb6464cb9a1f40f41a4252c50
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QseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens

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