Complementary Approaches to Combat Antibacterial Resistance: Metal-binding Small Molecules and Quaternary Ammonium Compounds Público

Abstract

Antibiotic resistance is a complex problem that has a far-reaching and destructive impact on life including health care, agriculture, and food-handling industries. All classes of antibiotics currently in use inhibit the same few biological targets allowing for rapid bacterial resistance development. With this in mind, my dissertation focuses on synthesizing and investigating natural products and small molecules that may inhibit bacteria in new ways. One area of my research is focused on investigating siderophores which are small iron-binding secondary metabolites that contribute to bacteria’s pathogenicity. Alternatively, a general method for sterilization is still needed for surfaces to keep food production centers and hospitals clean. Quaternary Ammonium Compounds (QACs) provide a broad-spectrum class of antibiotics that allow for bacterial killing without hitting a specific metabolic target by perturbing and lysing phospholipid membranes leading to cell death. Unfortunately, resistance to QACs are also on the rise and as such warrant further investigation into resistance mechanisms and the development of more potent compounds with novel structures.

Table of Contents

1 Introduction ........................................................................................................................................... 1

2. Synthesis and Biological Investigation of Iron-binding Natural Products ................................................ 1

2.1 Bacterial Iron Acquisition and Storage ............................................................................................... 1

2.2 Iron Uses and Functions ...................................................................................................................... 2

2.3 Siderophores ....................................................................................................................................... 4

2.3.1. Pyochelin ..................................................................................................................................... 5

2.4 Ulbactins ............................................................................................................................................. 7

2.4.1. Isolation ....................................................................................................................................... 7

2.4.2. Biosynthetic Route to Ulbactin ................................................................................................... 9

2.4.3. First Total Synthesis of Ulbactin F ........................................................................................... 11

2.4.4. Metal-binding studies ................................................................................................................ 17

2.4.5. Biological Investigation of Ulbactin F ...................................................................................... 21

2.4.6. Analog Design and Synthesis ................................................................................................... 23

2.5 Watasemycins and Thiazostatins ...................................................................................................... 25

2.5.1. Isolation of Thiazostatins and Watasemycins ........................................................................... 25

2.5.2. Progress Towards the Total Synthesis of Watasemycins and Thiazostatins ....................... 27

2.6 Conclusion ........................................................................................................................................ 38

2.7 References ......................................................................................................................................... 38

3. Quaternary Ammonium Compounds ........................................................................................................ 1

3.1 General QAC Structure and Mechanism of Action ...................................................................... 1

3.2 Polymeric Quaternary Ammonium Compounds (polyQACs) ...................................................... 3

3.2.1. The Haldar Group ................................................................................................................. 3

3.2.2. The Finn Group ..................................................................................................................... 5

3.2.3. The Tiller Group ................................................................................................................... 6

3.3 QACs as small molecules ............................................................................................................. 9

3.3.1. Commercial QACs ................................................................................................................ 9

3.3.2. Aminosterols as QACs .......................................................................................................... 9

3.3.3. Repurposing Known Antibiotics ......................................................................................... 12

3.3.2.1 Vancomycin Analogs by the Boger Lab ................................................................................. 12

3.3.2.2. Polymyxin B Analogs with the Pires Lab .............................................................................. 14

3.3.2. Minbiole-Wuest Labs: Collaborative QAC Development .................................................. 20

3.3.3.1. TMEDA Inspired QACs: the start of a beautiful thing .......................................................... 21

3.4. QAC Resistance .......................................................................................................................... 32

3.5. QAC activity against clinically isolated bacteria ........................................................................ 37

3.5.1. Acinetobacter baumannii .................................................................................................... 39

3.5.2. Pseudomonas aeruginosa .................................................................................................... 42

3.5.3. Future Experimentation ....................................................................................................... 44

3.6 Conclusions ....................................................................................................................................... 47

3.7 References ......................................................................................................................................... 47

4. Supporting Information ....................................................................................................................... 55

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Palabra Clave	QAC Antibiotic Siderophore Natural Product
Committee Chair / Thesis Advisor	William M. Wuest, Emory University
Committee Members	Simon B. Blakey, Emory University David G. Lynn, Emory University

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