USING CHEMICAL TOOLS TO UNRAVEL SMALL-MOLECULE BASED COMMUNICATION BETWEEN SPECIES

Life on earth is heavily based on chemical communication between cells. Quorum sensing enables unicellular organisms to coordinate their behavior and function in such a way that they can adapt to changing environments and compete, as well as coexist, with multicellular organisms. A prime example of this phenomenon is displayed by the opportunistic pathogen Pseudomonas aeruginosa, which causes disease in immunocompromised humans. Quorum sensing in this pathogen is mediated by binding of the transcriptional activator, LasR, to its ligand 3-oxo-C₁₂-HSL, leading to biofilm formation and secretion of virulence factors. We are targeting QS in P. aeruginosa and other pathogens with various chemical tools, such as a set of electrophilic probes that are designed to bind QS receptors covalently, leading to inhibition of QS regulated gene expression. We use these probes as molecular tools to obtain new insights into the mechanisms of activation and deactivation of bacterial quorum sensing.

Furthermore, we recently found that certain QS molecules and other natural products can also directly affect the behavior of other bacterial species as well as that of eukaryotes. Diverse eukaryotes have been found to react strongly to the presence of these compounds (often initiating counter-warfare to jam bacterial communication), however, to date no eukaryotic protein has been identified that binds bacterial QS molecules. We have synthesized and evaluated a set of `tag-free` probes to isolate and identify such receptors, in order to unravel mechanisms that govern these important interkingdom signaling events. We have also discovered several previously unknown signaling molecules from plants that interfere with bacterial communication.