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Targeting QseC signaling and virulence for antibiotic development.

Rasko, DA, Moreira, CG, Li, DER, Reading, NC, Ritchie, JM, Waldor, MK, Williams, N, Taussig, R, Wei, S, Roth, M , Hughes, DT, Huntley, JF, Fina, MW, Falck, JR and Sperandio, V (2008) Targeting QseC signaling and virulence for antibiotic development. Science, 321 (5892). pp. 1078-1080.

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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.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine > Department of Microbial and Cellular Sciences
Authors :
Rasko, DA
Moreira, CG
Reading, NC
Ritchie, JM
Waldor, MK
Williams, N
Taussig, R
Wei, S
Roth, M
Hughes, DT
Huntley, JF
Fina, MW
Falck, JR
Sperandio, V
Date : 22 August 2008
DOI : 10.1126/science.1160354
Uncontrolled Keywords : Animals, Anti-Bacterial Agents, Enterohemorrhagic Escherichia coli, Escherichia coli Infections, Escherichia coli Proteins, Francisella tularensis, Gene Expression Regulation, Bacterial, Gram-Negative Bacterial Infections, Mice, Norepinephrine, Phosphorylation, Protein Kinases, Rabbits, Salmonella Infections, Animal, Salmonella typhimurium, Signal Transduction, Small Molecule Libraries, Sulfonamides, Tularemia, Virulence Factors
Depositing User : Symplectic Elements
Date Deposited : 28 Mar 2017 14:41
Last Modified : 31 Oct 2017 14:30

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