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The Identification and Characterization of Novel Antibacterial Compounds Via Target-Based and Whole Cell Screening Approaches

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The Identification and Characterization of Novel Antibacterial Compounds Via Target-Based and Whole Cell Screening Approaches THE IDENTIFICATION AND CHARACTERIZATION OF NOVEL ANTIBACTERIAL COMPOUNDS VIA TARGET-BASED AND WHOLE CELL SCREENING APPROACHES BY NORA RENEE WANG DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate College of the University of Illinois at Urbana-Champaign, 2011 Urbana, Illinois Doctoral Committee: Professor Paul J. Hergenrother, Chair Professor Wilfred A. van der Donk Professor Scott K. Silverman Assistant Professor Martin D. Burke ABSTRACT The emergence of multidrug-resistant bacterial infections in both the clinical setting and the community has created an environment in which the development of novel antibacterial compounds is necessary to keep dangerous infections at bay. While the derivatization of existing antibiotics by pharmaceutical companies has so far been successful at achieving this end, this strategy is short-term, and the discovery of antibacterials with novel scaffolds would be a greater contribution to the fight of multidrug-resistant infections. Described herein is the application of both target-based and whole cell screening strategies to identify novel antibacterial compounds. In a target-based approach, we sought small-molecule disruptors of the MazEF toxin-antitoxin protein complex. A lack of facile, continuous assays for this target required the development of a fluorometric assay for MazF ribonuclease activity. This assay was employed to further characterize the activity of the MazF enzyme and was used in a screening effort to identify disruptors of the MazEF complex. In addition, by employing a whole cell screening approach, we identified two compounds with potent antibacterial activity. Efforts to characterize the in vitro antibacterial activities displayed by these compounds and to identify their modes of action are described. ii ACKNOWLEDGMENTS It is with much gratitude that I acknowledge several people whose support and friendship have made this thesis possible. First, I would like to thank my advisor, Paul Hergenrother, for his helpful ideas and suggestions, motivating discussions, and constant encouragement to live up to my greatest potential as a professional researcher. I am also indebted to the many past and current members of the Hergenrother lab whose questions and criticisms were a constant stimulus to expand my scientific knowledge and revise my research directions. In particular, I would like to thank Dr. Jason Thomas whose patience and guidance were instrumental to my early development as a researcher of molecular biology. In addition, Dr. Elizabeth Halvorsen, Julia Williams, Dr. Mirth Hoyt, and Dr. Christina Thompson facilitated the completion of this thesis both by providing scientific advice and ideas and by offering personal support, encouragement, and friendship. The animal studies described in this thesis were made possible by the assistance of Quinn Peterson, whose training and help was graciously offered whenever it was needed. I would also like to show my gratitude to my family whose love, encouragement, and faith were great sources of strength in difficult and trying times. Last but certainly not least, I would like to thank my husband, Ezra Eibergen, for being patient, understanding, distracting, and motivating throughout the most enjoyable and productive years of my graduate career. iii TABLE OF CONTENTS Chapter 1: The Discovery and Development of Novel Antibiotics for the Treatment of Multidrug-Resistant Infections .................................................................................................................. 1 1.1. Multidrug-resistant infections ............................................................................................................ 1 1.1.1. Methicillin-resistant S. aureus (MRSA) ...................................................................................... 1 1.1.2. Vancomycin-resistant enterococci (VRE) .................................................................................. 3 1.1.3. Pseudomonas aeruginosa and Acinetobacter baumannii ........................................................... 3 1.2. The current state of antibiotics ........................................................................................................... 4 1.2.1. Antibiotic scaffolds ..................................................................................................................... 6 1.2.2. Antibiotic targets ......................................................................................................................... 7 1.2.2.a. The inhibition of DNA replication by quinolones............................................................... 8 1.2.2.b. The inhibition of transcription by rifamycins ..................................................................... 9 1.2.2.c. The inhibition of bacterial translation by antibiotics ........................................................... 9 1.2.2.c.1. Bacterial translation ................................................................................................. 9 1.2.2.c.2. Tetracyclines .......................................................................................................... 11 1.2.2.c.3. Aminoglycosides .................................................................................................... 11 1.2.2.c.4. Chloramphenicol .................................................................................................... 12 1.2.2.c.5. Oxazolidinones ....................................................................................................... 13 1.2.2.c.6. Macrolides .............................................................................................................. 13 1.2.2.c.7. Streptogramins ....................................................................................................... 14 1.2.2.c.8. Fusidic acid ............................................................................................................ 16 1.2.2.d. The inhibition of cell wall biosynthesis by β-lactams ....................................................... 17 1.2.2.e. The inhibition of cell wall biosynthesis by glycopeptides ................................................ 18 1.2.2.f. The disruption of cell walls by daptomycin ...................................................................... 18 1.2.2.g. The inhibition of folic acid biosynthesis by sulfonamides ................................................ 18 1.3. Antibacterial discovery and development ......................................................................................... 19 1.3.1. Target-based antibiotic discovery ............................................................................................... 19 iv 1.3.1.a. High-throughput screening ................................................................................................ 20 1.3.1.b. Structure-based design ...................................................................................................... 21 1.3.2. Antibiotic discovery through whole cell screening approaches ................................................ 21 1.3.3. Antibiotic development ............................................................................................................. 22 1.3.3.a. Minimum inhibition concentration (MIC) determination ................................................. 23 1.3.3.b. Hemolytic assays as tools to identify nonspecific membrane disruptors .......................... 24 1.3.3.c. The effect of serum on antibacterial activity ..................................................................... 25 1.3.3.d. Resistance frequency determination ................................................................................. 27 1.3.3.e. Cytotoxicity ....................................................................................................................... 28 1.3.3.f. Spectrum of activity ........................................................................................................... 29 1.3.3.g. Bactericidal antibacterial activity ...................................................................................... 30 1.3.3.h. Mechanism of action elucidation ...................................................................................... 32 1.3.3.h.1. Potassium leakage ....................................................................................................... 32 1.3.3.h.2. Macromolecular synthesis assays ............................................................................... 33 1.3.3.h.3. Resistant mutant analysis ............................................................................................ 35 1.3.3.h.4. Target overexpression ................................................................................................. 36 1.3.3.i. Animal studies ................................................................................................................... 36 1.4. Conclusions and outlook ................................................................................................................... 40 1.5. References ........................................................................................................................................ 40 Chapter 2: The Development of a High-Throughput Assay for MazF Activity and its Application in a Screen for Disruptors of MazEF ................................................................................. 51 2.1. Introduction .....................................................................................................................................
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