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Felix Ekness ABSTRACT A Synthetic Biology Approach to Engineering Bacterial Two- Component Systems for Sensor Development and Discovery of Anti-Virulence Agents by Felix Ekness Bacterial two-component systems (TCSs) are the largest family of signal transduction pathways that enable bacteria to sense a diversity of stimuli including small peptides, environmental pollutants, and light. Canonical TCSs are composed of a transmembrane sensor histidine kinase (SK) that converts stimulus detection into phosphorylation of a cognate response regulator (RR). Upon phosphorylation, the cytoplasmic RR binds target output promoters, hereby modulating gene expression. TCSs are valuable sensors for synthetic biology due to their diverse sensing capabilities and straightforward transduction of detected stimulus into transcriptional regulation. TCSs are also emerging targets for novel therapeutic development due to their extensive role in regulating bacterial virulence and antibiotic resistance. Although TCSs are exciting sensors for synthetic biology and targets for therapeutic applications, most TCSs remain difficult to harness for applications and study due to output promoters that are unknown, subject to cross- regulation, or silent in heterologous hosts. In the first portion of my work, I develop a method to overcome the hurdles in characterizing and utilizing TCSs as biosensors. Through the framework of synthetic biology, I demonstrate that the two largest families of RR DNA binding domains (DBDs) can be interchanged with remarkable flexibility, enabling the corresponding TCSs to be rewired to synthetic output promoters. In collaboration with Kristina Daeffler, we exploit this plasticity to eliminate cross-regulation and in collaboration with Brian Landry, we un-silence a gram-negative TCS in a gram-positive host and engineer a sensor with over 1,300-fold activation. In collaboration with Kathryn Brink, we also apply DBD swapping to screen uncharacterized Shewanella oneidensis TCSs in Escherichia coli, leading to the discovery of a novel pH sensor. In the second portion of my work, I demonstrate a method for identifying inhibitors of a virulence regulating TCS. This work focuses on the methicillin-resistant Staphylococcus aureus (MRSA) virulence regulating TCS SaeRS. I first heterologously express saeRS in Bacillus subtilis to remove the native, confounding regulation of the TCS and its output promoter. I then screen heterologous SaeRS against a diverse 1,593 small molecule library to identify inhibitors of its signaling. A lead compound emerged from the screen as an effective inhibitor of SaeRS signaling, leading to decreased exoprotein secretion and virulence from treated MRSA similar to MRSA lacking saeRS. My work described herein should accelerate 1) fundamental TCS studies and the engineering of a large family of biosensors with diverse applications and 2) the discovery of new anti-virulence compounds. Acknowledgments I first want to thank my advisor Dr. Jeff Tabor for consistently challenging me, being forthright with me, and refining my scientific skills. While at times I may not have relished to hear your critiques, I am without a doubt a better scientist because of them. Thank you for being patient with me even after the nth mislabeled plot and thank you for your wonderful restaurant suggestions. I never expected Houston to have such a vibrant culinary scene. I next want to thank all of the incredible members of the Tabor Lab. You are all incredibly talented people and were instrumental in my success. Specifically, I want to thank Dr. Prabha Ramakrishnan, Dr. Karl Gerhardt, Dr. Sebastián Castillo-Hair, Dr. Lucas Hartsough, Dr. Brian Landry, Kathryn Brink, Dr. Kristina Daeffler, Dr. John Sexton, Lauren Gambill, Dr. Evan Olson, Dr. Shridhar Jayanthi, and Dr. Nicholas Ong. Graduate school is a marathon and without ya’ll I would be downright exhausted. Thank you for sharing countless beers with me, thank you for commiserating with me, and most of all, thank you for all of the wonderful nights spent singing karaoke at PJ’s. My thesis research has been highly collaborative and it would not have been as impactful if it were not for the work of Dr. Sebastian Schmidl, Katri Sofjan, Dr. Kristina Daeffler, Kathryn Brink, Dr. Brian Landry, Dr. Karl Gerhardt, Nikola Dyulgyarov, and Ravi Sheth on the rewiring two-component system (TCS) publication and for the MRSA expertise of Catherine Leasure, Dr. Andrew Monteith, Clare Laut, and Dr. Eric Skaar. I especially want to thank Kristina and Kathryn for their work on discovering a novel pH sensing TCS and Katri Sofjan for the tremendous number of plasmids she assembled for the TCS rewiring paper, a truly herculean effort. Additionally, I want to thank my fellow inaugural cohort of the Systems, Synthetic, and Physical Biology graduate students: Dr. Josh Atkinson, Dr. Brianna Kuypers iii iv Jayanthi, Dr. Robert (Tyler) McLaughlin, Dr. Dongya Jia, Dr. Juexio Wang, and Qian Mei. During our first year we bonded over countless hours and even an overnight or two attempting to complete our Physical Biology homework. While those homework assignments are long forgotten, I will always remember each one of you. I made lasting friendships with y’all and I am excited to see where your careers take you. Thank you for setting an exemplary example for future cohorts and also thank you to those cohorts that followed us. You all made this program into a vibrant, interdisciplinary powerhouse for systems, synthetic, and physical biology research. To my parents, Christiane Ekness and Ralph Ekness, thank you for your unconditional love. Thank you for your unwavering support of all my goals and for understanding the rigors of graduate school. No matter what time of day or night I needed your support or advice, you were always there for me. Last, but certainly not least, I want to thank my wonderful girlfriend Grace Tegeler. You have been an unwavering pillar of support for which I cannot thank you enough. Your incredible love and kindness mean the world to me and you and your family made me feel at home in Houston. Thank you. Contents Acknowledgments .................................................................................. iii Contents .................................................................................................. v List of Figures ...................................................................................... viii List of Tables .......................................................................................... x List of Abbreviations ............................................................................. xii Chapter 1 Introduction ........................................................................... 1 Abstraction of DNA into parts and genetic circuits ................................... 1 De novo bio-computing and bio-production using genetic circuits ............. 2 TCSs as inputs into genetic circuits ........................................................... 3 The role of TCSs in bacterial virulence ...................................................... 5 Chapter 2 Rewiring bacterial two-component systems by modular DNA binding domain swapping ........................................................................ 8 Author contributions and acknowledgements ............................................. 9 Introduction ................................................................................................ 9 Results ....................................................................................................... 13 2.3.1. Identification of OmpR/PhoB crossover points ................................ 13 2.3.2. OmpRDBD swapping is general .......................................................... 21 2.3.3. TorRDBD can be modularly swapped ................................................. 23 2.3.4. DBD swapping does not perturb TCS signaling ............................... 23 2.3.5. DBD swapping the NarL/FixJ family .............................................. 25 2.3.6. DBD swapping can un-silence TCSs in distant hosts ....................... 32 2.3.7. DBD swapping eliminates output promoter cross-regulation ........... 34 2.3.8. DBD swapping enables TCS input discovery ................................... 35 Discussion .................................................................................................. 40 Chapter 3 Identifying inhibitors of the MRSA pathogenesis regulating sensor SaeRS via heterologous expression and screening ...................... 44 Author contributions and acknowledgements ............................................ 44 v vi Introduction ............................................................................................... 45 Results ....................................................................................................... 47 3.3.1. Heterologous expression of SaeRS in B. subtilis ............................... 47 3.3.2. Heterologous SaeRS detects native stimulus .................................... 49 3.3.3. Inhibitor discovery of heterologous SaeRS ....................................... 53 3.3.4. Lead inhibitors are molecularly diverse ............................................ 55 3.3.5. Lead inhibitors canonically signal through SaeRS ............................ 59 3.3.6. NSC97920 and NSC33005 bind SaeS in vitro ................................... 63 3.3.7. NSC97920 decreases MRSA virulence .............................................. 65 Discussion and Future Directions .............................................................
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