Targeting QseC signaling and virulence for antibiotic development.
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.
Rasko
David A
DA
Department of Microbiology, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA.
Moreira
Cristiano G
CG
Li
De Run
de R
Reading
Nicola C
NC
Ritchie
Jennifer M
JM
Waldor
Matthew K
MK
Williams
Noelle
N
Taussig
Ron
R
Wei
Shuguang
S
Roth
Michael
M
Hughes
David T
DT
Huntley
Jason F
JF
Fina
Maggy W
MW
Falck
John R
JR
Sperandio
Vanessa
V
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
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