led209 and Tularemia

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.

Topics: Animals; Anti-Bacterial Agents; Enterohemorrhagic Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Francisella tularensis; Gene Expression Regulation, Bacterial; Gram-Negative Bacterial Infections; Histidine Kinase; Mice; Norepinephrine; Phosphorylation; Protein Kinases; Rabbits; Salmonella Infections, Animal; Salmonella typhimurium; Signal Transduction; Small Molecule Libraries; Sulfonamides; Tularemia; Virulence Factors