Journal Article

Targeting QseC Signaling and Virulence for Antibiotic Development

Huntley, Jason F, Fina, Maggy W, Taussig, Ron, Moreira, Cristiano G, Falck, John R, Waldor, Matthew K, Rasko, David A, Roth, Michael, Hughes, David T, Wei, Shuguang, Williams, Noelle, Reading, Nicola C, Sperandio, Vanessa, Ritchie, Jennifer M, Li, De Run

2008

Overview

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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Animals / Anti-Bacterial Agents - administration & dosage / Anti-Bacterial Agents - pharmacology / Anti-Bacterial Agents - therapeutic use / Antibacterial agents / antibacterial properties / Antibiotics / Antibiotics. Antiinfectious agents. Antiparasitic agents / Bacteria / bacterial infections / bacterial proteins / Biological and medical sciences / Biomedical research / Development strategies / drugs / Enterohemorrhagic Escherichia coli - drug effects / Enterohemorrhagic Escherichia coli - genetics / Enterohemorrhagic Escherichia coli - metabolism / Enterohemorrhagic Escherichia coli - pathogenicity / Escherichia coli Infections - drug therapy / Escherichia coli Proteins - antagonists & inhibitors / Escherichia coli Proteins - genetics / Escherichia coli Proteins - metabolism / Francisella tularensis - drug effects / Francisella tularensis - genetics / Francisella tularensis - metabolism / Francisella tularensis - pathogenicity / Gene expression / Gene Expression Regulation, Bacterial - drug effects / Genes / Gram-Negative Bacterial Infections - drug therapy / Histidine Kinase / Infections / Liver / Medical sciences / Mice / Microbiology / Molecules / Norepinephrine - metabolism / Pathogens / Pharmacology. Drug treatments / Phosphorylation / phosphotransferases (kinases) / Protein Kinases - genetics / Protein Kinases - metabolism / protein phosphorylation / Rabbits / Salmonella Infections, Animal - drug therapy / Salmonella typhimurium - drug effects / Salmonella typhimurium - genetics / Salmonella typhimurium - metabolism / Salmonella typhimurium - pathogenicity / Sensors / Signal transduction / Signal Transduction - drug effects / Small Molecule Libraries / Spleen / Sulfonamides - administration & dosage / Sulfonamides - chemistry / Sulfonamides - pharmacology / Sulfonamides - therapeutic use / toxicity / Tularemia - drug therapy / Virulence / Virulence Factors - genetics