Jam the Signal

Many bacterial pathogens sense that they are in a potential host because they can detect adrenergic molecules. These organisms share a sensor kinase that picks up the signal and relays it to virulence gene loci, thus kicking in the responses needed to ensure bacterial establishment. This pathway makes a good target for broad-spectrum antibiotic development because virulence inhibition should not present a strong selective pressure for resistance. Rasko et al. have had some success with this approach using a nontoxic small-molecule inhibitor of the sensor kinase QseC, which blocks signaling in a sensitive and specific manner. In animal models, the inhibitor was somewhat effective against gastrointestinal infections with enterohemorrhagic E. coliand Salmonella typhimurium. Encouragingly, the lead molecule was more effective against the systemic pathogen Francisella tularensis: A single oral dose protected 80% of infected mice from death.D. A. Rasko, C. G. Moreira, D. R. Li, N. C. Reading, J. M. Ritchie, M. K. Waldor, N. Williams, R. Taussig, S. Wei, M. Roth, D. T. Hughes, J. F. Huntley, M. W. Fina, J. R. Falck, V. Sperandio, Targeting QseC signaling and virulence for antibiotic development. Science321, 1078-1080 (2008). [Abstract][Full Text]