AI-3 Inhibitors as treatment for bacterial infections

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DESCRIPTION (provided by applicant): Bacteria communicate with each other via a system of signals known as quorum sensing. In recent years it has been demonstrated that this complex system of communication can include not just bacterial produced signals, but also host derived signals to control gene expression of virulence in pathogenic species. This proposal combines the expertise of five laboratories to develop compounds that compromise bacterial quorum sensing. By targeting quorum sensing we decrease the possibility of the development of resistance as it is not an essential biological process and thus negative selective pressure will be minor. We have identified a promising compound that inhibits the virulence of enterohemorrhagic E. coli and Salmonella species causing numerous food poisoning syndromes, as well as Francisella tularensis, the causative agent of tularemia by interfering with quorum sensing. These three diverse organisms, and potentially many others, can all be targeted by a single compound due to the presence of a widely conserved membrane bound receptor protein. Preliminary data suggests that this compound is specific for bacterial systems at concentrations in the picomolar range and has no obvious adverse effects on the host. In addition to the single compound that we have significant preliminary data for a number of alternative distinct compounds have also been identified and may be further developed. Our consortium contains the expertise to rationally develop this or an alternative compound into effective broad-spectrum inhibitor of virulence rendering the bacteria harmless.