Synthesis and Biological Investigation of Natural Product-Inspired Antimicrobial Compounds Pubblico

Abstract

Antibiotic resistance poses an alarming threat to public health. Over time, bacteria continually evolve and develop drug resistance, evading commonly used antibiotics. It is therefore necessary to synthesize novel antimicrobials with unique mechanisms of actions to overcome this problem. Compounds isolated from nature often show unique abilities to this end, and can be synthesized and modified to create new therapeutic agents. Quaternary ammonium compounds (QACs) comprise an important class of molecules due to their widespread use as antiseptic agents both commercially and in the household. Tricepyridinium bromide, a QAC natural product with a unique structure, showed promising inhibitory activity against S. aureus upon its initial isolation, prompting our investigation into its biological activity and mechanism of action. An efficient and reproducible synthetic route was devised to access tricepyridinium bromide as well as four different analogues. The resulting products then underwent biological analysis, and their inhibitory activity was compared to that of two commercially available QACs: cetylpyridinium chloride (CPC) and benzalkonium chloride (BAC). It was found that tricepyridinium and select analogues showed selectivity towards grampositive bacteria while also maintaining little to no hemolytic activity. In addition, the relationship between tricepyridinium and the QacR transcription factor responsible for regulating a QAC resistance pathway was investigated using molecular modeling. Our studies showed that tricepyridinium and shorter-chain N-alkyl analogs may preferentially bind to this transcription factor, thereby conferring QAC resistance. We also sought to better understand the potential bioactivity of several newly isolated lumazine peptides, one of which possessed isonitrile functionality. Isonitriles are unique in their ability to chelate metal, which we hypothesized could work as a way to attenuate bacterial virulence. Our current work focuses on synthesizing several isonitrile-functionalized lumazine peptides with the intention of studying the effects of this functional group on the bioactivity of these molecules. 

Table of Contents

1. Antibiotics: The Story So Far .....................................................................................................1

1.1. Bacteria and Antibiotics in Everyday Life ............................................................................1

1.2. The Antibiotic and Bacterial “Arms Race”...........................................................................1

1.3. Fighting Superbugs ...............................................................................................................4

2. Tricepyridinium Bromide Inspired QACs ..................................................................................5

2.1. Novel QAC Discovery ..........................................................................................................5

2.2. Proposed Mechanism of Action and Analogue Design ........................................................6

2.3. Synthesis................................................................................................................................8

2.4. Biological Investigation ......................................................................................................10

2.5. Outcomes.............................................................................................................................14

3. Lumazine peptides.....................................................................................................................15

3.1. Discovery and Biological Significance ...............................................................................15

3.2. Analogue Design and Methods...........................................................................................17

3.3. Future Directions.................................................................................................................22

4. Experimental..............................................................................................................................23

4.1. General Remarks.................................................................................................................23

4.2. Experimental Procedures Tricepyridinium Bromide and Analogue Synthesis...................23

4.3. Biological Testing ..............................................................................................................33

4.4. Experimental Procedures for Lumazine Peptides ...............................................................35

4.5. Spectral Data .......................................................................................................................41

5. References..................................................................................................................................72

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Organic
Parola chiave	synthesis
Committee Chair / Thesis Advisor	Wuest, William, Emory University
Committee Members	Lysaker, John, Emory University McDonald, Frank, Emory University

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