Targeting QseC signaling and virulence for antibiotic development

David A. Rasko; Cristiano G. Moreira; Run Li De; Nicola C. Reading; Jennifer M. Ritchie; Matthew K. Waldor; Noelle S Williams; Ronald Taussig; Shuguang Wei; Michael G Roth; David T. Hughes; Jason F. Huntley; Maggy W. Fina; J R Falck; Vanessa Sperandio

doi:10.1126/science.1160354

Targeting QseC signaling and virulence for antibiotic development

David A. Rasko, Cristiano G. Moreira, Run Li De, Nicola C. Reading, Jennifer M. Ritchie, Matthew K. Waldor, Noelle S Williams, Ronald Taussig, Shuguang Wei, Michael G Roth, David T. Hughes, Jason F. Huntley, Maggy W. Fina, J R Falck, Vanessa Sperandio

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419 Scopus citations

Abstract

Many bacterial pathogens rely on a conserved membrane histidine sensor kinase, QseC, to respond to host adrenergic signaling molecules and bacterial signals in order to promote the expression of virulence factors. Using a high-throughput screen, we identified a small molecule, LED209, that inhibits the binding of signals to QseC, preventing its autophosphorylation and consequently inhibiting QseC-mediated activation of virulence gene expression. LED209 is not toxic and does not inhibit pathogen growth; however, this compound markedly inhibits the virulence of several pathogens in vitro and in vivo in animals. Inhibition of signaling offers a strategy for the development of broad-spectrum antimicrobial drugs.

Original language	English (US)
Pages (from-to)	1078-1080
Number of pages	3
Journal	Science
Volume	321
Issue number	5892
DOIs	https://doi.org/10.1126/science.1160354
State	Published - Aug 22 2008

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@article{199e3227561d48758110c59b97de9e31,

title = "Targeting QseC signaling and virulence for antibiotic development",

abstract = "Many bacterial pathogens rely on a conserved membrane histidine sensor kinase, QseC, to respond to host adrenergic signaling molecules and bacterial signals in order to promote the expression of virulence factors. Using a high-throughput screen, we identified a small molecule, LED209, that inhibits the binding of signals to QseC, preventing its autophosphorylation and consequently inhibiting QseC-mediated activation of virulence gene expression. LED209 is not toxic and does not inhibit pathogen growth; however, this compound markedly inhibits the virulence of several pathogens in vitro and in vivo in animals. Inhibition of signaling offers a strategy for the development of broad-spectrum antimicrobial drugs.",

author = "Rasko, {David A.} and Moreira, {Cristiano G.} and De, {Run Li} and Reading, {Nicola C.} and Ritchie, {Jennifer M.} and Waldor, {Matthew K.} and Williams, {Noelle S} and Ronald Taussig and Shuguang Wei and Roth, {Michael G} and Hughes, {David T.} and Huntley, {Jason F.} and Fina, {Maggy W.} and Falck, {J R} and Vanessa Sperandio",

note = "Funding Information: The authors have financial support from Zhejiang province key science and technology innovation team (Grant No. 2013TD13), Zhejiang provincial natural science foundation of China (Grant No. LQ16H160006 & LQ16H160007), National Science Foundation for Distinguished Young Scholars of China (Grant No. 81602047, 81601710).",

year = "2008",

month = aug,

day = "22",

doi = "10.1126/science.1160354",

language = "English (US)",

volume = "321",

pages = "1078--1080",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "5892",

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TY - JOUR

T1 - Targeting QseC signaling and virulence for antibiotic development

AU - Rasko, David A.

AU - Moreira, Cristiano G.

AU - De, Run Li

AU - Reading, Nicola C.

AU - Ritchie, Jennifer M.

AU - Waldor, Matthew K.

AU - Williams, Noelle S

AU - Taussig, Ronald

AU - Wei, Shuguang

AU - Roth, Michael G

AU - Hughes, David T.

AU - Huntley, Jason F.

AU - Fina, Maggy W.

AU - Falck, J R

AU - Sperandio, Vanessa

N1 - Funding Information: The authors have financial support from Zhejiang province key science and technology innovation team (Grant No. 2013TD13), Zhejiang provincial natural science foundation of China (Grant No. LQ16H160006 & LQ16H160007), National Science Foundation for Distinguished Young Scholars of China (Grant No. 81602047, 81601710).

PY - 2008/8/22

Y1 - 2008/8/22

N2 - Many bacterial pathogens rely on a conserved membrane histidine sensor kinase, QseC, to respond to host adrenergic signaling molecules and bacterial signals in order to promote the expression of virulence factors. Using a high-throughput screen, we identified a small molecule, LED209, that inhibits the binding of signals to QseC, preventing its autophosphorylation and consequently inhibiting QseC-mediated activation of virulence gene expression. LED209 is not toxic and does not inhibit pathogen growth; however, this compound markedly inhibits the virulence of several pathogens in vitro and in vivo in animals. Inhibition of signaling offers a strategy for the development of broad-spectrum antimicrobial drugs.

AB - Many bacterial pathogens rely on a conserved membrane histidine sensor kinase, QseC, to respond to host adrenergic signaling molecules and bacterial signals in order to promote the expression of virulence factors. Using a high-throughput screen, we identified a small molecule, LED209, that inhibits the binding of signals to QseC, preventing its autophosphorylation and consequently inhibiting QseC-mediated activation of virulence gene expression. LED209 is not toxic and does not inhibit pathogen growth; however, this compound markedly inhibits the virulence of several pathogens in vitro and in vivo in animals. Inhibition of signaling offers a strategy for the development of broad-spectrum antimicrobial drugs.

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VL - 321

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JO - Science

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Targeting QseC signaling and virulence for antibiotic development

Abstract

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