Targeting QseC signaling and virulence for antibiotic development

  • Science. 2008 Aug 22;321(5892):1078-80. doi: 10.1126/science.1160354.
David A Rasko  1 ,  Cristiano G Moreira ,  De Run Li ,  Nicola C Reading ,  Jennifer M Ritchie ,  Matthew K Waldor ,  Noelle Williams ,  Ron Taussig ,  Shuguang Wei ,  Michael Roth ,  David T Hughes ,  Jason F Huntley ,  Maggy W Fina ,  John R Falck ,  Vanessa Sperandio
Affiliations
  • 1. Department of Microbiology, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA.
PMID: 18719281 DOI: 10.1126/science.1160354
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.

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