Natural Product Inspired Complementary Approaches to Counter Antimicrobial Resistance: Synthetic and Biological Investigations of Antibacterial Small Molecules Open Access

Allen, Ryan (Spring 2023)

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Natural products are small molecules produced by living organisms for a specific purpose in an ecological niche. These small molecules oftentimes have complex structures and activities that lend themselves to development into novel therapies for diseases. Development of these novel therapies is increasingly important with the rise of antibiotic resistant bacteria that threaten modern day medicine. To this end, the total synthesis and modification of natural products and natural product-like scaffolds to identify novel mechanisms of action and activities has been undertaken. To identify novel mechanisms of action for the development of antibiotics, the total synthesis of the mindapyrroles and investigation into their photoactivity for use in affinity-based protein profiling experiments was explored. To combat prevalent disinfectant resistance, our collaborators in the Minbiole Lab at Villanova University synthesized novel quaternary ammonium compounds (QACs) to test against common pathogenic bacteria. Inspired by this work, we undertook the total synthesis of the ianthelliformisamines, a class of polyamine natural products, for the development of novel QAC scaffolds. 

Table of Contents

Chapter 1: Introduction to Natural Product Antimicrobials and the Rise of Antibiotic Resistance.. 1

1.1 The History of Natural Product Antimicrobials. 2

1.1.1      Uses in Traditional Medicine. 2

1.1.2      The Golden Age of Antibiotic Discovery. 3

1.2     The Rise of Antibiotic Resistance. 5

1.2.1      Mechanisms of Antibiotic Resistance. 5

1.3     Current Methods to Combat Antibiotic Resistance. 8

1.3.1      Repurposing Previously Active Scaffolds. 9

1.3.2      Combination Therapies and Polypharmacology. 10

1.3.3      Discovery of Novel Mechanisms of Action. 12

1.3.4      The Wuest Lab Approach. 13

1.4     Conclusions. 14

Chapter 2: The Mindapyrroles. 19

2.1 Isolation and Background of Pyoluteorin and the Mindapyrroles. 19

2.1.1      History of Pyoluteorin. 19

2.1.2      Isolation of the Mindapyrroles. 22

2.1.3      Methods for Determining Mechanism of Action. 23

2.1.4      Affinity-Based Protein Profiling Overview.. 25

2.2    The 2-Benzoylpyrrole Moiety. 27

2.2.1      2-Benzoylpyrrole in Antibacterials. 27

2.2.2      Photoactivity of 2-Benzoylpyrrole. 27

2.3    Total synthesis of Mindapyrroles A and B.. 30

2.3.1      Retrosynthetic Design. 30

2.3.2      Total synthesis of Pyoluteorin and Biomimetic Dimerization Attempts. 31

2.3.3      The Benzoyl Chloride Dimer Route. 34

2.3.4      The Friedel-Crafts Inspired Route. 36

2.3.5      Total Synthesis of Mindapyrroles A and B. 47

2.4    Initial Photochemical Investigations of Pyoluteorin. 48

2.5    Biological Investigations of Pyoluteorin and the Mindapyrroles. 49

2.6     Conclusions and Future Work. 51

2.7    Chapter 2 References. 51

Chapter 3: Quaternary Ammonium Compounds. 57

3.1    Introduction to Quaternary Ammonium Compounds: Past to Present. 57

3.1.1      Initial Discovery and Widespread Use through Covid-19. 58

3.1.2      Development of QAC Resistance. 59

3.1.3      Novel QAC Scaffolds. 61        Polymeric QAC Scaffolds. 62        QAC Appended Antibiotics. 63        Small Molecule QACs. 64

3.2     Appending Quaternary Ammoniums to Polymyxin B to Broaden Activity. 67

3.3     Investigations of Activity-Rigidity Relationships in Bispyridinium QACs. 71

3.4     Explorations of Ferrocene-Containing QACs. 74

3.5     Trivalent Sulfonium Compounds versus Quaternary Ammonium Compounds. 78

3.6     Exploring Amphiphilic Disinfectant Resistance in Clinical Isolates. 81

3.6.1      A. baumannii 83

3.6.2      P. aeruginosa. 88

3.7    Developing Novel QAC Scaffolds from a Natural Product: Quaternization of Ianthelliformisamine C  89

3.7.1      Activity of the Ianthelliformisamines and Potential for Polypharmacological Development 90

3.7.2      Total Synthesis of Ianthelliformisamine C and QAC Analogs. 91

3.7.3      Biological Activity of Ianthelliformisamine C and its QAC Derivatives. 96

3.8     Conclusions. 97

3.9     Chapter 3 References. 98

Chapter 4: Discussion.. 105

Chapter 5: Experimental Details. 108

5.1     General Information. 108

5.1.1      General Chemical Materials and Methods. 108

5.1.2      General Biological Materials and Methods. 108        Minimum Inhibitory Concentrations (MIC) Assay. 108        Hemolysis20 Assay. 109

5.2     Synthetic Procedures. 109

5.2.1      Chapter 2. 109

5.2.2      Chapter 3. 129

5.3    Characterization. 136

5.3.1      Chapter 2. 136

5.3.2      Chapter 3. 167

5.4         References 181

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