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Publication Date

Spring 2018

Degree Type

Thesis - Campus Access Only

Degree Name

Master of Science (MS)

Department

Chemistry

Advisor

Laura C. Miller Conrad

Keywords

antibiotic resistance, photoaffinity labeling, Pseudomonas aeruginosa, pyocyanin, quorum sensing, virulence

Subject Areas

Chemistry; Organic chemistry

Abstract

Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium affecting those with weakened immune systems including burn victims, surgical implant patients and those with cystic fibrosis. Due to the rise in antibiotic resistance, our lab has developed an antivirulence approach to combat this pathogen. The current, and increasingly less effective, method is the antimicrobial approach that either kills the bacteria or prevents bacterial growth. An antivirulence strategy deactivates pathogenicity, here through the inhibition of redox-active pyocyanin, a key virulence factor produced by P. aeruginosa, which then allows the host’s immune system to clear the infection on its own. We have developed a small molecule that disrupts production of pyocyanin through an unknown mechanism. Our primary objective is to identify the molecular target with a photoaffinity labeling (PAL) approach by incorporating a photoreactive diazirine ring on our inhibitor as well as a bioorthogonal reactive group, which is helpful for protein purification. We have successfully synthesized and characterized a key intermediate and have made progress toward the target compound. By using affinity chromatography and proteomics, we will identify candidates for the molecular target that can be confirmed in further studies. We ultimately aim to characterize additional processes that control pyocyanin production. This information could provide new targets for future antivirulence therapeutics to combat this threatening pathogen.

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