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.
authors: Department of Microbiology, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA.
authors: David A
authors: DA
authors: Rasko
authors: Cristiano G
authors: CG
authors: Moreira
authors: De Run
authors: de R
authors: Li
authors: Nicola C
authors: NC
authors: Reading
authors: Jennifer M
authors: JM
authors: Ritchie
authors: Matthew K
authors: MK
authors: Waldor
authors: Noelle
authors: N
authors: Williams
authors: Ron
authors: R
authors: Taussig
authors: Shuguang
authors: S
authors: Wei
authors: Michael
authors: M
authors: Roth
authors: David T
authors: DT
authors: Hughes
authors: Jason F
authors: JF
authors: Huntley
authors: Maggy W
authors: MW
authors: Fina
authors: John R
authors: JR
authors: Falck
authors: Vanessa
authors: V
authors: Sperandio
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D054324:Enterohemorrhagic Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000188:drug therapy; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005604:Francisella tularensis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D000071677:Histidine Kinase; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D012481:Salmonella Infections, Animal / Q000188:drug therapy; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014406:Tularemia / Q000188:drug therapy; D037521:Virulence Factors / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; C531088:LED209; C455504:QseC protein, E coli; D054852:Small Molecule Libraries; D013449:Sulfonamides; D037521:Virulence Factors; D011494:Protein Kinases; D000071677:Histidine Kinase; D009638:Norepinephrine