Novel Chemical Strategies to Overcome Antimicrobial Resistance Restricted; Files Only

Abstract

Antimicrobial resistance (AMR) poses one of the most urgent challenges to modern medicine. Decades after the “Golden Age” of antibiotic discovery, the emergence of multidrug-resistant microbes threatens to outpace our ability to develop new therapeutics. This thesis explores novel chemical strategies to address this growing crisis through both medicinal chemistry and total synthesis approaches. The first chapter investigates metal chelation as a promising antibacterial strategy against Gram-negative ESKAPE pathogens, particularly in Pseudomonas aeruginosa and Acinetobacter baumannii. By disrupting essential metal homeostasis, metallophores and siderophore-conjugated antibiotics impair bacterial physiology and virulence while reducing selective pressure for resistance. Building on this foundation, the second chapter describes a medicinal chemistry campaign targeting carbapenem-resistant A. baumannii. This work focused on optimizing analogs of the lipoprotein transport inhibitor fendiline to improve potency and solubility. Using structure–activity relationship (SAR) studies, we identified analogs with increased stability and measurable antibacterial activity in permeability-enhanced A. baumannii strains. These findings highlight the potential of lipoprotein trafficking inhibition as a novel antibacterial mechanism and provide a platform for future analog development. The final chapter details progress toward the first total synthesis of the natural product brasilidine A, a potent antifungal and cytotoxic indole alkaloid isolated from Nocardia brasiliensis. Brasilidine A’s unexplored mechanism of action and dual antifungal–antitumor activity makes it an attractive scaffold for future analog synthesis and mode-of-action studies. Together, these projects reflect complementary approaches to combat AMR: designing synthetic molecules that exploit new bacterial vulnerabilities and advancing the total synthesis of natural products with underexplored bioactivity.

Table of Contents

Chapter 1: Antimicrobial resistance and novel strategies for therapeutics 8

1.1 Introduction to Antimicrobial Resistance 8

1.2 Metal Chelation as a novel strategy against A. baumannii and P. aeruginosa 12

Chapter 2: Medicinal Chemistry Approaches to Carbapenem-Resistant Acinetobacter Baumannii 18

2.1 Introduction to Carbapenem-Resistant A. baumannii 18

2.2 Analog Synthesis 21

2.3 Biological Activity 29

2.4 Future Directions 31

Chapter 3: Efforts Towards the Total Synthesis of Natural Product Brasilidine A 33

3.1 Introduction to Antifungal Resistance 33

3.2 Attempted Total Synthesis 35

3.3 Reflections and Conclusions 41

Supporting Information for Chapter 2 43

Supporting Information for Chapter 3 60

References 65

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Organic
Keyword	Chemistry
Committee Chair / Thesis Advisor	William Wuest, Emory University
Committee Members	Jose Soria, Emory University Hiram Maxim, Emory University

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