Overcoming Antibacterial Resistance through Synthesis of Small Molecules Targeting Efflux Mechanisms Pubblico
Mahoney, Andrew (Spring 2023)
Published
Abstract
Antibiotic resistance remains a dire threat to humanity. Mechanisms through which this resistance occurs in bacteria are intricate but warrant extensive study due to the widespread ramifications of this crisis. Efflux of small molecule antibiotics is a particularly understudied mechanism due to limitations in structural biology and screening techniques, but has been identified for virtually every class of antibiotic. This thesis details efforts to probe structural features and substrate recognition of bacterial efflux systems, and to examine potential ways to circumvent them.
The first chapter contextualizes bacterial resistance development, presented first from an evolutionary standpoint, detached from its implications on human health. It is followed by an anthropocentric perspective, analyzing humanity’s understanding of microorganisms’ roles in disease throughout history. It concludes with analysis of the prevalence of bacterial resistance development and strategies for slowing this phenomenon.
The second chapter details synthetic efforts towards novel promysalin analogs. This natural product is a potent metabolic inhibitor of Pseudomonas aeruginosa, but suffers from several key structural liabilities, allowing for bacterial resistance development. Methods to synthesize and biologically examine analogs designed to circumvent two hypothesized mechanisms (efflux and hydrolysis) of promysalin resistance are described.
The third chapter describes investigations into the P. aeruginosa efflux pump MexXY-OprM. Because of the relative lack of information regarding substrate recognition and efflux by MexXY-OprM, we undertook collaborative efforts to understand this system, entailing computational screening, biological analysis, and synthesis of a number of berberine analogs with potential as efflux pump inhibitors.
The fourth chapter explores natural product tricepyridinium, a molecule whose antibiotic activity may be attributed either to membrane permeabilization or DNA intercalation. Biological and computational analysis of the natural product and four synthetic analogs designed to investigate this class of molecules’ cellular target revealed that several of these analogs showed evasion of bacterial efflux.
The fifth chapter investigates inhibition of bacterial metal chelation, a promising avenue for treatment. Synthesis of ten recently-identified lumazine peptides hypothesized to function as fungal metallophores was thus pursued. While inhibition assays revealed no antibacterial activity for these molecules, efforts are ongoing to determine the role of these compounds in the producing species.
Table of Contents
Table of Contents
Chapter 1 - Introduction to Bacterial Infections and Resistance. 1
1.1 An Evolutionary Perspective. 1
1.2 An Anthropocentric Perspective. 7
1.3 Antibiotic Resistance. 11
1.4 Chapter 1 References 16
Chapter 2 - Investigation of Promysalin Resistance via Rationally Guided Analog Design. 23
2.1 Introduction. 23
2.2 Synthesis. 37
2.3 Biological Investigation. 47
2.4 Chapter 2 Concluding Remarks and Future Directions. 50
2.5 Chapter 2 References 52
Chapter 3 - Optimization of berberine-derived alkaloids as MexXY-OprM Inhibitors and Aminoglycoside Adjuvants 54
3.1 Introduction. 54
3.2 Computational Screening. 62
3.3 Synthesis. 63
3.4 Concluding Remarks and Future Directions. 81
3.5 Chapter 3 References 82
Chapter 4 - Concise synthesis of tricepyridinium bromide derivatives. 86
4.1 Introduction. 86
4.2 Synthesis. 95
4.3 Biological and Computational Investigation. 100
4.4 Chapter 4 Concluding Remarks and Future Studies. 105
4.5 Chapter 4 References 106
Chapter 5 - A bioinspired approach to synthesize metal-chelating lumazine peptides 110
5.1 Introduction. 110
5.2 Synthesis. 121
5.4 Chapter 5 Concluding Remarks and Future Directions. 135
5.4 Chapter 5 References 135
Chapter 6 - Experimental Details. 141
6.1 Supplementary schemes, figures, and tables. 141
6.2 Biological assays 145
6.3 Chemistry. 151
6.4 Chapter 6 References 240
Chapter 7 Appendix. 241
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