| Quorum sensing is a process bacteria utilize to detect their population density and regulate collective behavior via gene expression and/or repression. Quorum sensing is mediated by secretion and detection of small molecules, referred to as autoinducers (AIs). System two quorum sensing has been implicated in interspecies bacterial communication, mediating signaling among a broad range of species via production of S-4,5-dihydroxy-2,3-pentanedione (DPD) by the DPD synthase LuxS. DPD is the parent of a series of interconverting molecules, any of which may have the potential to be the active signal, collectively referred to as autoinducer two (AI-2).;The rapid development of bacterial resistance to conventional therapies highlights the need for new approaches to address bacterial pathogenicity. Chemical modulation of interspecies bacterial quorum sensing provides a different strategy than conventional antibiotics. Two strategies for modulating system two quorum sensing are addressed herein.;We have designed and synthesized a series of eight carbocyclic analogs of DPD targeting the Vibrio harveyi DPD sensor protein LuxP and the Salmonella typhimurium DPD transporter protein LsrB. We have identified one strong agonist and one weak agonist of the V. harveyi LuxP quorum sensing receptor. Our findings suggest that any modification disrupting the hydroxyl network of the natural substrate will have a negative impact on binding affinity. S. typhimurium LsrB showed no response to these analogs.;We then designed, synthesized and evaluated a series of competitive inhibitors of the DPD synthase, LuxS. These inhibitors were prepared via rational design and synthesis of analogs of the natural substrate of LuxS, S-ribosylhomocysteine (SRH). We identified two moderate inhibitors and one weak inhibitor of LuxS. Our findings suggest that effective inhibitors of LuxS require an appropriate geometry to bind in the active site of LuxS, polarizable electron density at the thioether position of SRH, the presence of a metal-chelating group, and the presence of an amino acid group. Each of these components appears to contribute to optimum binding of competitive inhibitors to LuxS. |
