Academic and Applied Considerations of the Population and Evolutionary Dynamics of Bacteria, Antibiotics, and Bacteriophage Öffentlichkeit
Berryhill, Brandon (Spring 2025)
Abstract
In 1920, infectious diseases accounted for one in three deaths worldwide. Thanks to advances in treating bacterial infection, particularly the development of antibiotics, this number has declined to one in four globally and one in seven in the Western world. However, the rise of antibiotic resistance threatens to reverse these gains. Given the increase in infections with antibiotic-resistant pathogens, there is a growing need to develop a more comprehensive understanding of antibiotic chemotherapy and other methodologies for preventing and treating diseases. Addressing this challenge requires a deeper understanding of (i) the population and evolutionary dynamics of bacteria under antibiotic treatment and the contribution of the innate immune system, (ii) the potential of alternative therapies such as bacteriophages, (iii) the combined effects of bacteriophages and antibiotics in optimizing treatment outcomes, and (iv) nonpharmacologic strategies to limit pathogen spread. Tremendous progress has been made in these subjects, however the knowledge generated by these findings is primarily molecular and mechanistic. There remains a knowledge gap in these topics, which must be addressed through population and evolutionary dynamic studies.
My dissertation explores these four critical areas using theoretical and experimental approaches with key bacterial pathogens, particularly Escherichia coli and Staphylococcus aureus, in investigating the population and evolutionary dynamics of antibiotics, bacteriophages, and bacteria. Through a series of studies, my investigations advance our understanding of bacterial infection treatments and the interplay between antimicrobial treatment regimens. Yet, as with all scientific inquiry, each finding raises new questions.
Table of Contents
Chapter 1. Introduction ………………………………………………………………………… 1
Chapter 2. What’s the Matter with MICs: Bacterial Nutrition, Limiting Resources, and Antibiotic Pharmacodynamics ………………………………………………………… 9
Supporting Information …………………………………………………………… 37
Chapter 3. Theoretical Considerations and Empirical Predictions of the Pharmaco- and Population Dynamics of Heteroresistance ………………………………………… 48
Supporting Information …………………………………………………………… 73
Chapter 4. The evolution of heteroresistance via small colony variants in Escherichia coli following long term exposure to bacteriostatic antibiotics ………………………… 89
Supporting Information …………………………………………………………… 115
Chapter 5. Antibiotic killing of drug-induced bacteriostatic cells ………………………… 131
Chapter 6. The Future of Phage Therapy in the United States …………………………… 143
Chapter 7. The book of Lambda doesn’t tell us that naturally occurring lysogens of Escherichia coli are likely to be resistant and not only immune to phage coded by their prophage …………………………………………………………………… 170
Supporting Information …………………………………………………………… 192
Chapter 8. Enteric Populations of Escherichia coli are Likely to be Resistant to
Phages Due to O Antigen Expression ……………………………………………… 207
Supporting Information …………………………………………………………… 235
Chapter 9. The ecological consequences and evolution of retron-mediated suicide as a way to protect Escherichia coli from being killed by phage …………………… 248
Supporting Information …………………………………………………………… 270
Chapter 10. Evaluating the potential efficacy and limitations of a phage for joint
antibiotic and phage therapy of Staphylococcus aureus infections ………………… 276
Supporting Information …………………………………………………………… 302
Chapter 11. The role of innate immunity, antibiotics, and bacteriophages in the course of bacterial infections and their treatment .…………………………… 325
Supporting Information …………………………………………………………… 351
Chapter 12. Summary and Conclusions ….………………………………………………… 362
Appendix 1. Using Lambda phages as a proxy for pathogen transmission in hospitals … 369
Supporting Information …………………………………………………………… 392
Appendix 2. A Bacteriophage-based Validation of a Personal Protective Equipment
Doffing Procedure to be Used with High Consequence Pathogens ……………… 394
Supporting Information …………………………………………………………… 424
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