Leveraging Organic Synthesis to Disrupt and Understand Essential Bacterial Processes Open Access

Abstract

Since the serendipitous discovery of penicillin in 1928, antibiotics have revolutionized modern medicine and the way we treat bacterial infections, saving numerous lives in cases that were previously viewed as death sentences. However, this so-called “Golden-Age” of antibiotics has come to a screeching halt in recent years due to the discovery of increasing numbers of antibiotic-resistant bacteria and the lack of discovery of novel antibiotics to treat such infections. The threat of antibiotic resistance is now one of the biggest threats to the medical community, and thus finding new ways to combat these pathogens is now a major priority for both the Center for Disease Control and Prevention and the World Health Organization. With this in mind, my dissertation focuses on drawing inspiration primarily from natural sources to synthesize organic small molecules with the goal of perturbing or understanding essential bacterial processes. To this end, I have focused on two main pathogens that are key contributors to life-threatening and often times hospital-acquired infections particularly immunocompromised patients: Pseudomonas aeruginosa and Staphylococcus aureus. I will first give a more detailed introduction to antibiotics and antibiotic resistance, laying the foundation for the rest of my dissertation, which will first discuss two projects aimed at combatting and further understanding P. aeruginosa followed by two projects focused on targeting S. aureus.

Table of Contents

Table of Contents

1.    INTRODUCTION

1.1.     Bacteria

1.2.     The Early Days of Antibiotics

1.3.     The Golden Era of Antibiotics

1.4.     The Post-Golden Era and the Threat of Antibiotic Resistance

1.4.1.      Broad Spectrum vs. Narrow Spectrum Treatments

1.4.2.      The ESKAPEE Pathogens

1.5.     A Brief Interlude into Novel Antibiotic Treatments

1.5.1.      Designing Species-Specific Antibiotics

1.5.2.      Trojan Horse Antibiotics

1.5.3.      Prevention of Bacterial Infections

1.5.4.      Anti-Persister Antibiotics

1.5.5.      Novel Scaffolds: Trans-Decalin-Containing Antimicrobials

1.6.     My Approach to This Dissertation

1.7.     References

2.    TARGET BASED DESIGN AND SYNTHESIS OF A NEW PROMYSALIN ANALOG

2.1.     Background

2.1.1.      Isolation of Promysalin⁷

2.1.2.      Total Synthesis of Promysalin⁸

2.1.3.      SAR Studies⁹

2.1.4.      Target Identification¹⁰

2.1.5.      Species Specificity of Promysalin

2.2.     Side Chain Analogs

3.2.1.      Computational Analysis

3.2.2.      Terminal Aryl Analogs

3.3.     Compound 2.01

3.3.1.      Synthesis of 2.01

3.3.2.      Biological Evaluation of 2.01

3.4.     New Terminal Aryl Analogs

3.5.     References

3.    SYNTHESIS AND BIOLOGICAL EVALUATION OF IRON-BINDING BACTERIAL METABOLITES

3.1.     The Role of Iron in Bacteria

3.2.     Bacterial Iron Acquisition

3.2.1.      Methods for Iron Uptake

3.2.2.      Siderophores

3.3.     Pseudomonas Metabolites

3.3.1.      Pyochelin and Pyoverdine

3.3.2.      Pyochelin Biosynthesis

3.3.3.      Pyochelin Biosynthetic Shunt Products

3.3.4.      IQS and Other Pseudomonad Metabolites

3.4.     Hypothesis for Pyochelin Shunt Metabolites

3.5.     Investigation of Pyochelin Shunt Metabolites

3.5.1.      Synthesis

3.5.2.      Iron-Binding Evaluation

3.5.3.      Biological Evaluation

3.6.     Conclusions and Broader Impacts

3.7.     Oxazoline and Oxazole Analogs

3.7.1.      Synthesis

3.7.2.      Fe^III-Binding Properties

3.7.3.      Biological Evaluation

3.7.4.      Conclusions

3.8.     Acinetobacter Siderophores

3.8.1.      Acinetobactin Biosynthesis

3.8.2.      Synthesis of 3.22

3.8.3.      Iron-Binding Properties

3.8.4.      Biological Evaluation

3.8.5.      Conclusions

3.9.     References

4.    INVESTIGATION OF QUATERNARY AMMONIUM COMPOUNDS (QACS)

4.1.     (Methicillin-Resistant) Staphylococcus aureus and Prevention of Infections

4.2.     QAC Background

4.2.1.      Previous Work

4.2.2.      Wuest and Minbiole

4.3.     3-Alkylpyridine Alkaloids (3-APAs)

4.3.1.      Arctic 3-APAs

4.3.2.      Previous Biological and Synthetic Investigations

4.4.     Haliclocyclins as QACs

4.5.     Synthesis of Haliclocyclins

4.6.     Biological Evaluation of Haliclocyclins

4.7.     Conclusions and Further SAR Efforts

4.8.     References

5.    EVALUATING THE EFFECT OF BROMINATION ON INDOLE-CONTAINING ANTIBIOTICS

5.1.     Indole as a Bacterial Metabolite

5.2.     The Potential of Indole-Containing Antibiotics

5.2.1.      Indole-Containing Anti-Persister Compounds

5.2.2.      Indole-Containing Anti-Biofilm Compounds

5.2.3.      Halogenated Indole Antibiotics

5.3.     Brominated Bis- and Tris- Indole Antimicrobial Compounds

5.3.1.      Isolation and Biological Activity of Tulongicin and Dihydrospongotine C

5.3.2.      Synthetic Library

5.3.3.      Conclusions and Future Directions

5.4.     References

6.    SUPPORTING INFORMATION

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	Antibiotics
Committee Chair / Thesis Advisor	William Wuest, Emory University
Committee Members	Frank McDonald, Emory University Huw Davies, Emory University

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