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1.2 an Overview of Phage Therapy Development of Natural and Engineered Bacteriophages as Antimicrobials by Robert James Citorik BSc. in Microbiology, University of New Hampshire (2008) Submitted to the Microbiology Graduate Program in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY June 2018 @ Massachusetts Institute of Technology 2018. All rights reserved. Signature redacted A uthor ............................. Microbiology Graduate Program Signature reaacted May 25, 2018 C ertified by .................. .............. Timothy K. Lu Associate Professor of Biological Engineering and Electrical Engineering and Computer Science Thesis Supervisor Signature redacted A ccepted by ............................ Kristala L. Jones Prather MASSACHUSMlS INSTrTUTE OF TECHNOWGY rthur D. Little Professor of Chemical Engineering Chair of Microbiology Program JUL 09 2018 LIBRARIES ARCHIVES 2 Development of Natural and Engineered Bacteriophages as Antimicrobials by Robert James Citorik Submitted to the Microbiology Graduate Program on May 25, 2018, in partial fulfillment of the requirements for the degree of Doctor of Philosophy Abstract One of the major public health concerns of the modern day is the emergence and spread of extensively antibiotic-resistant pathogens. We have already seen the arrival of infections caused by bacteria resistant to all available antibiotics in the therapeutic arsenal. In addition, we have learned much of the incredible importance of the microbial communities that cohabit our bodies, and of how perturbations to these communities can lead to long-lasting health effects. Bacteriophages may pro- vide a solution for both of these problems, in that they are narrow-spectrum and can be used to specifically kill target microbes without disrupting whole commu- nity structure through off-target effects. Here, various approaches to creating phage- based therapeutics are explored, including the isolation and application of naturally occurring wild-type phages, the conversion of temperate phages to obligately lytic phages to permit their use as a resource in phage therapeutics, and the creation of programmable, sequence-specific antimicrobials through phage-mediated genetic pay- load delivery. These efforts are expected to contribute to the field by expanding the approaches available to develop next-generation, phage-based antimicrobials. Thesis Supervisor: Timothy K. Lu Title: Associate Professor of Biological Engineering and Electrical Engineering and Computer Science 3 4 Acknowledgments I would like to take this opportunity to first express my sincere gratitude to all of the teachers, friends, family, and other role models who have helped and inspired me to complete this leg of my journey. Without all of you, none of this would have been possible. To Tim Lu, my supervisor and mentor for the past 7 years: I thank you for giving me the opportunity to explore exciting and creative science under your guidance. I recognize that being in this laboratory has been a unique experience, and that many are not given the same freedom and independence to pursue new ideas and explore interesting side projects. To my thesis committee members, Jim Collins, Eric Alm, and Deb Hung: I am grateful for all of your guidance and expertise in pursuing, as well as finishing, my PhD research. None of you needed to say yes when I asked for your time in this endeavor, and for this I am very thankful. I hope that our conversations continue beyond my time at MIT. To my program: I feel extremely lucky to have found the Microbiology Program at MIT, and I thank Alan Grossman for creating this opportunity for such interdisci- plinary research, as well as Bonnielee Whang for helping keep us in line and all those faculty who have helped to organize and lead the way. This unique program allowed me to venture beyond basic science research and enter into the exciting fields of bio- logical engineering and synthetic biology, where I have found an exciting interface in which to build upon my previous research in pathogenic microbiology. To my wife: Jenna, I would never have survived this experience without your support and understanding. Your effort and commitment to giving your all to your students, as well as your husband, is truly inspiring. This degree belongs to the both of us. I love you with all of my heart, and being able to start forever with you has been an unanticipated highlight of my graduate school tenure. If we can survive being a PhD student at MIT and an elementary school teacher working tireless hours, we can survive anything. On to the next chapter! 5 To my family: I thank my mother and father for instilling in me the drive that has brought me to where I am today, for I am certain that I am here because they cared about my education from the very first day of school. I know the days of getting help with homework are long gone, but those lessons in problem-solving, as well as how to look out for your children, will last a lifetime. I thank my brother and sister, as well as my brother- and sister-in-law, for always being there for me. They are the kind of support system crucial to success in any aspect of life. I also thank my grandparents and the others who have helped teach me lessons far beyond the realm of academia. To my friends and labmates: I thank you for your day-to-day support, from the little things to the major ones. From bringing joy to mundane tasks to having a drink after impressive failures. You are all the best. I cannot believe the number of lifelong friends I have made by spending too much time together in the lab. To Mark, I thank you for being a simultaneous peer, friend, and mentor. I hope that you have benefited even a fraction as much as I have from our lab bromance. To Area Four: I thank you for your caffeine. I have seen many baristas come and go during my tenure, but the coffee has stood the test of time. And to all those not specifically mentioned here: the people who have touched my life from my early years to today are countless, and the journey would never have been the same save for all of these interactions. So a final thank you goes out to the unnamed, whose influence neither of us may even remember, but who have helped me to be where I am today. And with these words, I will continue seeking to leave a positive mark on the world as I go forth and SCIENCE! 6 Contents 1 Introduction 13 1.1 Introduction ........ ................. ...... 13 1.2 An Overview of Phage Therapy .............. .... .. 13 1.3 Engineered Phages as Therapeutics and Tools for Health . ...... 16 1.4 New Phage Engineering Strategies ............. ...... 20 1.5 Bacteriophages and the Microbiome ............ ...... 22 1.6 Chapter Overviews ............ ......... ...... 24 2 Phages from Without: Isolation and Characterization of Phag E~s from the Environment 27 2.1 Introduction . ........ ........ ........ ...... 28 2.2 Isolation of Novel Bacteriophages ....... ....... ..... 29 2.3 Characterization of Bacteriophages ....... ........ ... 29 2.4 Murine Gastrointestinal Colonization Model .......... ... 33 2.5 D iscussion ........... ........... .......... 37 2.6 Experimental Details ....... ........ ........ ... 39 3 Phages from Within: Utilization of Prophages for Bacterial Target- ing 43 3.1 Introduction ...... ........ ........ ....... .. 44 3.2 Discovery and Characterization of <}Kpn852 ..... ........ 47 3.3 Construction of Lytic Phage Derivatives ....... ........ 50 3.4 D iscussion ............ .................... 54 7 3.5 Experimental Details ............ ............... 55 4 Phages born Anew: Using CRISPR Payloads to Create Sequence- Specific Antimicrobials 59 4.1 Introduction ........ ................................ 60 4.2 Transformation Assays for Validation .................. 62 4.3 Cell-Based Delivery .... ........... .......... ... 64 4.4 Phage-Based Delivery . ...... ...... ...... ...... .. 66 4.4.1 Toxin-Antitoxin Activation ........ ........ .... 69 4.5 Targeting Virulence Genes in Galleria mellonella Models of Infection 71 4.6 Population Sculpting ... ...... ....... ...... ..... 73 4.7 D iscussion ............ ............. ........ 74 4.8 Experimental Details .... ............ ........... 78 5 Conclusion 87 8 List of Figures 2-1 Plaque assay on propagation hosts .................... 31 2-2 Mutant derivative K6.2 shows probable capsule alteration ...... 31 2-3 Double-agar spotting assay for determining host range of inhibitory activity .. ....................... ......... 32 2-4 Visualization of selected bacteriophages by transmission electron mi- croscopy (TEM ) ... ............... ............ 34 2-5 Murine gastrointestinal colonization model ............... 36 2-6 Phage therapy reduces K. pneumoniae levels in murine gut . ..... 36 2-7 Phage <DKPNIH1-1 is not maintained in the gut ............ 37 3-1 Two disparate lifestyles for bacteriophages ..... .......... 44 3-2 Overview of yeast assembly for phage genome reconstruction ..... 46 3-3 K. pneumoniae KPNIH31 harbors a viable prophage ......... 48 3-4 Polishing of the <DKpn852 genome .................... 49 3-5 Phage <bKpn852 is a relative of E. coli phage N15 ........... 50 3-6 TEM visualization of K. pneumoniae phage <DKpn852 and E. coli phage N 15 .................... ............. 51 3-7 Phage <bKpn852 genome rebooting is inefficient in E. coli ....... 51 3-8 Overexpression of antirepressor antC in E. coli C-1 prevents lysoge- nization by phage N15 ...................... .... 52 3-9 Engineering an obligately lytic derivative of
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