Off-campus SJSU users: To download campus access theses, please use the following link to log into our proxy server with your SJSU library user name and PIN.

Publication Date

Fall 2022

Degree Type

Thesis - Campus Access Only

Degree Name

Master of Science (MS)

Department

Chemistry

Advisor

Laura Miller Conraid

Subject Areas

Chemistry

Abstract

The World Health Organization has designated the gram-negative opportunisticbacterium Pseudomonas aeruginosa as a high priority because of the threat it poses to human health. Therefore, the development of novel medicines is urgently required to combat the pathogen's multidrug-resistant infections. Targeting virulence is one method for creating novel therapeutic approaches. In P. aeruginosa phenazine-1-carboxylic acid (PCA) is synthesized by a phenazine biosynthetic pathway. PhzM and PhzS then transform PCA into pyocyanin, an important virulence factor. Our lab evaluated whether an antipyocyanin compound could inhibit one of the biosynthetic enzymes needed to synthesize PCA. To identify the molecular target more precisely, we also created a photoaffinity analog of the antipyocyanin molecule. ArnA, an enzyme involved in resistance to cationic antimicrobial peptides (CAPs) rather than phenazine regulation, was the top hit from the photoaffinity experiments. Because the arnBCADTEF pathway, alters lipid A in the outer membrane, is upregulated in resistant strains of P. aeruginosa, CAPs like colistin are ineffective in treating infections. We hypothesize that inhibiting the ArnA C-terminal domain may prevent outer membrane modification and make the bacteria sensitive to CAPs like colistin in combination therapy. While developing inhibitors of the enzyme is the ultimate aim, it is essential to first understand the kinetics of the enzyme. The development of new P. aeruginosa treatment strategies has benefited from the work of both projects.

Download

Available for download on Monday, March 20, 2028

Share

COinS