Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative nosocomial bacteria species that targets patients suffering from immune-compromising diseases, such as AIDS, cystic fibrosis, cancer, and severe burns. It utilizes density-dependent quorum sensing (QS) signaling pathways to produce virulence factors and biofilm, a major component of antibiotic resistance. While there are multiple QS pathways utilized by P. aeruginosa, the focus of this paper is on the las pathway, due to its importance in the regulation of other QS pathways and biofilm production. The LasR receptor binds with the natural autoinducer (AI), 3-oxo-dodecanoyl homoserine lactone (3O-C12-HSL), to initiate the production of virulence factors. The goal of this research is to use synthetic AIs to bind with LasR and regulate production of virulence factors. A synthetic tri-phenyl molecule, TP-1, known as an effective AI, has been used to gather insight into the binding site of LasR. The TP-1 molecule is comprised of a brominated core phenyl ring with two adjacent phenyl rings containing electronegative R-groups NO2 and Cl. The synthetic AIs in development are based on the TP-1 scaffolding, and contain electronegative R-groups on the adjacent phenyl rings. The five-step synthesis of the core molecule [(3,5-dibromo-2(methoxymethoxy)phenyl)methanimine] of TP-1 has been completed. Using the core molecule, development of the TP-1R molecule and a library of other synthetic autoinducers is underway. Regulation of QS activity in Pseudomonas aeruginosa will be analyzed using a LasR GFP reporter assay. As the library is developed, a structure-activity relationship study will be conducted, guiding the design for future analogs.

Designing small molecule autoinducers for investigation into the binding pocket of LasR

249th National Meeting (2015)

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