Natural Product-Inspired Strategies to Address Antibiotic Resistance in Pseudomonas aeruginosa Restricted; Files Only

Abstract

Antibiotic resistance is a critical threat to global health, with Pseudomonas aeruginosa standing out due to its intrinsic resistance mechanisms and adaptive capabilities. The natural product promysalin selectively inhibits P. aeruginosa by targeting primary metabolism, making it a promising scaffold for developing analogs and investigating the influence of metabolism on antibiotic susceptibility. This study employs an interdisciplinary approach of microbiology and synthetic organic chemistry to explore three strategies for combating antibiotic resistance in P. aeruginosa: combination therapies, antibiotic sensitization, and the development of narrow spectrum antibacterials. Combination studies revealed the metabolic basis of aminoglycoside activity and uncovered a synergistic interaction between promysalin and vancomycin. Further investigation into Gram-positive antibiotic sensitization in P. aeruginosa suggested mechanisms beyond membrane permeability. Additionally, promysalin was functionalized with distal aryl moieties to assess the role of π-π stacking in target engagement. Collectively, these findings enhance our understanding of P. aeruginosa biology and establish promysalin as a valuable tool for studying antibiotic resistance.

Table of Contents

Chapter 1: Introduction

Chapter 2. Selective inhibition of Pseudomonas aeruginosa metabolism in antibiotic combination studies

Chapter 3: Gram-positive antibiotic sensitization in Pseudomonas aeruginosa

Chapter 4: Target-guided synthesis of aryl functionalized promysalin analogs

Chapter 5: Experimental Details

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic Biology, Microbiology
Keyword	antibiotic resistance pseudomonas aeruginosa natural products
Committee Chair / Thesis Advisor	William Wuest, Emory University
Committee Members	Katherine Davis, Emory University Simon Blakey, Emory University

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