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Science 321 (5892): 1078-1080

Copyright © 2008 by the American Association for the Advancement of Science

Targeting QseC Signaling and Virulence for Antibiotic Development

David A. Rasko,1* Cristiano G. Moreira,1 De Run Li,2 Nicola C. Reading,1 Jennifer M. Ritchie,3 Matthew K. Waldor,3 Noelle Williams,2 Ron Taussig,4 Shuguang Wei,2 Michael Roth,2 David T. Hughes,1 Jason F. Huntley,1 Maggy W. Fina,4 John R. Falck,2,4 Vanessa Sperandio1,2{dagger}

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.

1 Department of Microbiology, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA.
2 Department of Biochemistry, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA.
3 Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4 Department of Pharmacology, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA.

* Present address: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

{dagger} To whom correspondence should be addressed. E-mail: vanessa.sperandio{at}utsouthwestern.edu


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