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Investigation Of The Pqse:rhlr Complex As A Target For Quorum Sensing Inhibition In Pseudomonas Aeruginosa
Derringer, Jesse
Derringer, Jesse
Abstract
Pseudomonas aeruginosa is responsible for tens of thousands of infections and thousands of deaths each year. While primarily infecting immunocompromised individuals and people with cystic fibrosis, the ability of P. aeruginosa to evade treatment with antibiotics makes it a significant clinical burden. The imminence of antibiotic resistance and stagnation of new antibiotic development spurs researchers to investigate new strategies for combatting P. aeruginosa infection. It is known that P. aeruginosa relies on quorum sensing, the chemical cell-cell communication process, to carry out pathogenic behaviors. Further, the interaction between two proteins, PqsE and RhlR, has been identified for its indispensable role in translating chemical signals into infection. By using an Escherichia coli reporter, small molecule libraries were screened to discover inhibitors of the PqsE:RhlR protein-protein interaction. Hit molecules were then confirmed using both in vitro and in vivo experiments. Fluorescence polarization and esterase assays measured the affinity of small molecule inhibitors for the active site of PqsE and the ability of these inhibitors to block enzyme activity. Cell-based assays in P. aeruginosa included measuring the effect hit molecules have on virulence factor production. Furthermore, E. coli and P. aeruginosa reporters were constructed to understand how PqsE influences RhlR transcription factor activity in a gene-specific manner. These experiments link gene expression in the newly built E. coli reporters with analogous virulence factor production in P. aeruginosa. Finding and characterizing quorum sensing inhibitors, as well as understanding the link between quorum sensing and virulence, opens the door to new ways of treating P. aeruginosa infections, not by killing the bacteria, rather by keeping them from coordinating pathogenic behaviors.
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2024-01-01
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Chemistry
DOI
https://dx.doi.org/10.21220/s2-9r3x-ak84