led209 and Escherichia-coli-Infections

Bacterial adhesion infection caused by medical materials in clinical application has become a serious threat, and it urgently needs new strategies to deal with these clinical challenges. In this work, LED209, a highly selective histidine sensor kinase inhibitor of Gram-negative bacteria, was covalently attached on cellulose membrane (CM) via click reaction. The data of contact angle measurements, ATR-FTIR and X-ray photoelectron spectroscopy confirmed the successful synthesis of LED-CM. In addition, the results of antibacterial activity of the membranes shown that LED-CM exhibited excellent anti-adhesion ability to Enterohemorrhagic Escherichia coli (EHEC), and significantly reduced the formation of bacterial biofilm. Importantly, LED-CM was able to repress the expression of virulence genes in EHEC. Furthermore, LED209-functionalized cellulose membrane indicated no cytotoxicity to mammalian cells. Hence, our present work demonstrated that CM modified with LED209 possessed markedly anti-adhesion activity against EHEC, which offered a potent antimicrobial material for combating bacterial infections.

Topics: Animals; Anti-Bacterial Agents; Bacterial Adhesion; Bacterial Outer Membrane Proteins; Biofilms; Cellulose; Enzymes, Immobilized; Escherichia coli Infections; Escherichia coli O157; Escherichia coli Proteins; Membranes, Artificial; Mice; Multienzyme Complexes; NIH 3T3 Cells; Sulfonamides

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