Inhibition of Quorum Sensing in Pseudomonas aeruginosa through the PqsE Active Site

Pseudomonas aeruginosa is a multi-drug-resistant pathogenic bacterium, meaning that most antibiotics cannot treat infections caused by these bacteria. With a lack of novel antibiotics coming into circulation, P. aeruginosa is a threat to global health amid the current antibiotic resistance crisis. P. aeruginosa utilizes a cell-to-cell communication mechanism called quorum sensing in order to produce toxins and form multicellular communities called biofilms. Quorum sensing in these bacteria depends on the interaction between the proteins PqsE and RhlR. Inhibiting this protein-protein interaction could turn off quorum sensing and allow P. aeruginosa infections to be more easily treated. This research project explored two methods of drug discovery: structurally-informed ligand derivatization and high-throughput screening to identify molecules that could potentially inhibit this quorum-sensing ability and allow for new methods to treat P. aeruginosa infections. This work led to the synthesis and evaluation of five novel PqsE inhibitors and the identification of three FDA-approved molecules from the screening process for further analysis.