The opportunistic pathogen Pseudomonas aeruginonsa has been shown to utilize quorum sensing to coordinate activation and repression of many unlinked genes in response to cell density.  P. aeruginonsa uses small signaling molecules, which are synthesized continually throughout cell growth, to determine cell density. Once a critical threshold concentration of these molecules has been reached, binding to a specific receptor occurs resulting in synchronized changes in gene expression. Both virulence factor production and formation of antibiotic resistant biofilms are known to be under quorum sensing control leading to infections that are difficult to eradicate.PQS, a quorum sensing signaling molecule used by P. aeruginonsa, and its biosynthetic precursor HHQ have been shown to bind the PqsR receptor. While PQS and HHQ bind PqsR, it is believed that they also interact with additional proteins regulating virulence factor production and biofilm formation.We present the results of chemical proteomic studies in which immobilized PQS and HHQ probes were used to identify unknown macromolecular biological targets of the two molecules. The design and synthesis of second-generation photoaffinity-based PQS and HHQ chemical probes for use in vivo is also presented and the results from both proteomic studies are compared. These studies are the first to identify that PQS binds MexG, a component of the MexG-OpmD efflux pump, which has previously been linked to quorum sensing, antibiotic susceptibility and virulence. As well as improving the current understanding of bacterial communication these studies also have the potential to uncover new drug targets for combating antibacterial resistance.

Chemical probes for studying cell-to-cell communication in bacteria

248th National Meeting (2014)

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