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Publication Date

Spring 2017

Degree Type

Thesis - Campus Access Only

Degree Name

Master of Science (MS)

Department

General Engineering

Advisor

Laura Miller Conrad

Subject Areas

Bioinformatics

Abstract

Multidrug resistant (MDR) strains of Pseudomonas aeruginosa are a growing threat to humans. P. aeruginosa coordinates a wide variety of behavior through the LasI/LasR quorum sensing pathway. This includes behavior that is virulent to host cells. Acyl homoserine lactones (AHLs) are autoinducers of the LasI/LasR pathway. After synthesis by LasI, a LuxI-type acyl homoserine lactone (AHL) synthase, AHLs are secreted to the extracellular space. They re-enter neighboring bacteria and activate the quorum sensing receptor LasR, the major transcriptional regulator for the pathway. By focusing on LasI inhibition, our research goal is to develop an antivirulence strategy against MDR strains of P. aeruginosa based on disrupting LasI/LasR quorum sensing pathway using small molecule inhibitors of LasI. This is expected to reduce AHL synthesis, induction of the LasI/LasR pathway, and subsequent virulent behavior. By simulating LuxI-type AHL synthases and docking them with AHL-like inhibitor analogs, we identify a subset of small molecule inhibitors for AHL synthases that may be useful in mitigating virulence in MDR strains of P. aeruginosa.

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