A Three-Pronged Approach to Combatting Antibiotic Resistance Open Access
Post, Savannah (Summer 2022)
Abstract
Widespread use of antibiotics and the decline of pharmaceutical investment has led to the proliferation of antibiotic resistance in many important diseases. Herein I discuss three different strategies that utilize small molecules to combat this growing problem: species-selective inhibition, combination therapies, and anti-virulence. Many currently utilized antibiotics are broad-spectrum, meaning that they target both Gram-positive and Gram-negative species. An alternative strategy is to take a more targeted approach wherein compounds selectively target a specific pathogen or group of pathogens, to protect the human microbiome. Promysalin is a natural product that exhibits species-selective inhibition against Pseudomonas aeruginosa, which has developed widespread clinical resistance. My research has elaborated on previous work in our group, and I have strategically developed several panels of analogs based on computational modeling, in search of more potent derivatives. I have also explored promysalin in combination with various antibiotics and other small molecules as a second strategy for combatting bacterial resistance. The final approach I explored to circumvent resistance emergence is the use of anti-virulence strategies. Virulence aids in bacterial pathogenicity but is not required for growth. By targeting these pathways instead of killing the bacteria, we are minimizing the selective pressure to mutate and develop resistance. The cahuitamycins are a group of natural products that inhibit biofilm formation in Acinetobacter baumannii, a known virulence behavior. My work has focused on the first total synthesis and analog development of these natural products. These findings have set the stage for future work in our lab investigating the mechanism of action of these new antimicrobial compounds.
Table of Contents
Table of Contents
Chapter 1. Introduction
1.1 Antibiotics and Resistance
1.1.1 Traditional Mechanisms of Action
1.1.2 Resistance Mechanisms
1.1.3 ESKAPE Pathogens
1.2 Alternative Approaches to Bacterial Inhibition
1.2.1 Species-Selective Inhibition
1.2.2 Combination Therapies
1.2.3 Anti-virulence
1.3 References
Chapter 2.___ Synthesis and Biological Investigation of Promysalin Alkyl Analogs
2.1. Introduction
2.2. Synthesis
2.3. Growth Inhibition
2.4. Computational Modeling
2.5. Conclusions
2.6. References
Chapter 3. Investigation of a Simplified Promysalin Analog for Antibiotic Synergy
3.1. Introduction
3.2. Synthesis & Growth Inhibition of Simplified Analog
3.3. Screen for Synergy with Traditional Antibiotics
3.4. Alternative Approaches to Bacterial Synergism
3.5. Conclusions & Future Directions
3.6. References
Chapter 4.___ Total Synthesis of the Reported Structure of the Cahuitamycins and Structural Isomers
4.1. Introduction
4.1.1. Acinetobacter baumannii
4.1.2. Cahuitamycin Prior Work
4.2. Total Synthesis & Structural Evaluation
4.2.1. Cahuitamycin E
4.2.2. Structural Evaluation of Cahuitcamycin A
4.3. Analog Synthesis
4.4. Conclusions & Future Directions
4.5. References
Chapter 5. Experimental Details
5.1. Promysalin Alkyl Analogs
5.1.1. Supporting Figures
5.1.1. Chemistry
5.1.3. Biology
5.1.4. Computation
5.2. Promysalin Synergy
5.2.1. Supporting Figures
5.2.2. Chemistry
5.2.3. Biology
5.3. Cahuitamycins
5.3.1. Supporting Figures
5.3.2. Chemistry
5.2.3. Biology
5.4. References
5.5. Spectral Data
About this Dissertation
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Primary PDF
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A Three-Pronged Approach to Combatting Antibiotic Resistance () | 2022-07-23 00:07:26 -0400 |
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Supplemental Files
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Spectral Data (Spectral data for synthetic compounds) | 2022-07-23 00:07:37 -0400 |
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