Membranes & Metals: Bacterial Targets to Fight Antibiotic Resistance Open Access

Zaremba, Cassandra (Fall 2022)

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The need for antibiotics with novel mechanisms of action has been a mounting problem for over a decade. In 2014, O’Neill released a mathematical analysis that predicted that antibiotic resistant infections may be the leading cause of death by 2050 if the situation remains unrectified. Although academic research in the analysis of novel antibiotic compounds has increased, there has been a lack of translation to commercialization in part due to strenuous approval processes from the Food and Drug Administration and lack of financial support from pharmaceutical companies. The larger antagonist in this story, however, is the constantly evolving bacteria. Bacteria have developed several mechanisms to evade the killing power of antibiotics: resistance and persistence. Resistance is a genetic alteration whereas persistence is phenotype change. To combat both issues, novel mechanisms of action need to be explored. Discussed herein, I analyze three small molecule scaffolds that serve as tool compounds to explore novel mechanisms of action: membrane perturbation and disruption of metal homeostasis.

Table of Contents

Chapter 1 – Introduction 1 Chapter 2 – Structure-Activity-Relationship Campaign of the synthetic retinoid, 72 CD437 Chapter 3 – Synthetic and Biological Investigations into Quaternary 106 Ammonium Compounds Chapter 4 – Synthetic and Biological Investigations into Simplified Analogs of SF2768 128 Chapter 5 – Supplementary Information 142 Appendix – Spectral Data 168

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