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Investigational Peptide-Based Therapeutics: Antibacterial Agents, Adjuvants and Combinations Thereof Against Gram-Negative Bacteria

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Investigational Peptide-Based Therapeutics: Antibacterial Agents, Adjuvants and Combinations Thereof Against Gram-Negative Bacteria Investigational peptide-based therapeutics: antibacterial agents, adjuvants and combinations thereof against Gram-negative bacteria by Ronald John Domalaon A Thesis submitted to the Faculty of Graduate Studies of The University of Manitoba in partial fulfilment of the requirements of the degree of DOCTOR OF PHILOSOPHY Department of Chemistry University of Manitoba Winnipeg, Manitoba, Canada Copyright © 2019 by Ronald Domalaon i ii Abstract Antimicrobial peptides represent a vast pool of biomolecules that may serve as the next generation of therapeutic agents. The alarming surge of multidrug-resistant bacterial pathogens able to repel and deactivate almost all clinically-used antibiotics drives our necessity to develop novel therapeutics, such as peptide-based agents. Arguably, the problem of antimicrobial resistance is more serious in Gram-negative bacteria (GNB), relative to Gram-positive bacteria, as they typically carry multiple chromosomal-mediated resistance mechanisms and possess an intrinsic mechanism that restricts the entry of most antibiotics. This intrinsic resistance mechanism in GNB consists of the outer (OM) and inner membranes (IM), and overexpressed multidrug efflux systems. The OM and IM impose an orthogonal constraint on the type of molecules able to traverse to the cytosol. The OM prevents the entry of large hydrophobic molecules while the IM prevents the diffusion of large hydrophilic molecules. Once the antibiotic enters the periplasm or the cytosol, it can then be efficiently expelled by a multitude of efflux pumps. Peptide-based agents, including naturally-occurring antimicrobial peptides and their mimics, usually target bacterial membranes. These membranotropic actions include perturbation of both the OM and IM (that can lead to lysis and intracellular component leakage), and sequestering of lipid components that may inactivate transmembrane proteins such as efflux pumps. The degree of membrane perturbation varies from each peptide, as some peptides result in overall membrane dissolution (lysis) while some induce only localized membrane disruption. My doctoral research work capitalized on this membranotropic mechanism to develop investigative peptide-based agents against GNB that act as stand-alone antibiotics or as helper molecules, called adjuvants, in combination with other established antibiotics. In this context, peptide-based adjuvants work in iii synergy through the enhancement of antibiotic cellular entry by either inducing localized imperfections (pores) in membranes, that allow diffusion of molecules, or sequestering lipid components surrounding efflux pumps, that prevent the debilitating action of efflux. My work took inspiration from amphiphilic membrane-acting antimicrobial peptides to develop potent short synthetic lead adjuvants that in combination with clinically-used antibiotics can effectively eradicate GNB. Peptide-based adjuvants in this thesis comprised of short proline-rich lipopeptides, dilipid ultrashort cationic lipopeptides and polymyxins derivatives. Specifically, polymyxin analogs in this thesis included dilipid polymyxins and polymyxin B3-tobramycin hybrid. The work described herein utilized these membranotropic adjuvants to revitalize the activity of antibiotics from intrinsic resistance of GNB. My doctoral research work presented herein follow a ‘sandwich thesis’ format. iv Acknowledgements If there is a moment where I could be granted the option to stop time, I wish it to be in this moment as I write my gratitude and reminisce about the good old times; for a man who do not look at his past is nothing but a fool who’s bound to nothingness. I would not be able to accomplish all this work without any support system, and I am very grateful for them. I am forever in debt to my supervisor, Dr Frank. Schweizer, for guiding me on this intellectual journey. He’s always there to advice when I’m in doubt, there to support when I needed help and there to steer my efforts towards excellence. A great mentor is someone who gives you freedom to learn from your mistakes and to celebrate glory from your initiative, but with an unwavering guidance whichever path you take. I could not ask for a better mentor! I am thankful to my advisory committee members Dr. George G. Zhanel, Dr. Joe O’Neil and Dr. Ayush Kumar for supporting my inquisitions in the multidisciplinary field of research. I value each member’s expertise and guidance towards my growth as an organic chemist learning biochemistry, microbiology, pharmaceutical and medical/life science. My journey will never be the same without the energetic and dynamic team of personnel in the Schweizer Research Group. I, without a doubt, believe that our group have been the most enthusiastic and liveliest group in our floor, if not our building. I thank all my research peers Xuan Yang, Temilolu Idowu, Nicole Nolasco, Dr. Yinfeng Lyu, Marie Haufroid, Camilo Fabra Prieto, v Dr. Makanjoula Ogunsina, Dr. Brandon Findlay, Dr. Navneet Chehal, Dr. Balakishan Gorityala, Dr. Goutam Guchhait, Dr. Sudeep Goswami, Dr. Yaozu Xu and Dr. Fan Zhang, for our camaraderie and help in the laboratory. I thank all the undergraduate students, Yaroslav Sanchak, Pavan Badogoo, Ruochen (Tony) Mao, Quinn Tays, Liam Berry, Liting Bi, Marc Brizuela, Oreofe (Grace) Okunnu, Joseph Rebizant and Danyel Ramirez, that I had the pleasure to directly supervise and foster their growth. I am very proud of these students’ progress and research accomplishments/publications. I thank the rest of undergraduate students to whom I may not supervise but have been constantly interacting with ever since, especially to Benchmen Trieu, Hangyi Pan, Lucas Vasas, Patrick Arevalo, Derek Ammeter, Heather Rossong and Danzel Ramirez. I will always cherish all the good and bad and the crazy moments I have with these individuals. I am very thankful to Liam Berry for joining our group and giving me the joy of mentoring a bright and astute junior, to whom will be continuing my legacy in peptide-based therapeutics within the group. Many thanks to the Chemistry Department of the University of Manitoba and all the individuals that I had the pleasure to interact with since my undergraduate degree. I am forever in debt to my second/academic-mom Krystyna Koczanski, to the ever nurturing Dr. Elena Smirnova and to my friend Dr. Horace Luong. These three individuals have been key figures on my growth, to whom I have modeled my academic, supervisorial and teaching styles. A big thanks to Sharon Mullen, Tricia Lewis and Keith Travis, along with all the support staff. I would also like to thank the Manitoba Health Research Council (MHRC), now called Research Manitoba, and the University of Manitoba for generously providing financial support throughout my graduate studies. vi More importantly, I give thanks to my immediate and extended family whom always proactively supported my study. Nothing compares to the extensive support system a Filipino family have for each other, especially my 50+-member family that reside in Winnipeg, MB, Canada. Many thanks to all my friends and peers, in the Philippines and in Canada. Lastly, I would like to thank my significant other for providing emotional support and understanding throughout my study. vii Table of Contents Chapter 1: Antimicrobial peptides as promising therapeutic agents ............................................. 1 1.1. Introductory remarks ............................................................................................................ 1 1.2. Contributions of authors ....................................................................................................... 1 1.3. Abstract ................................................................................................................................ 2 1.4. Antimicrobial peptides as an emerging class of antibacterials ............................................ 2 How do AMPs exert their biological function? ....................................................................... 5 1.5. Short AMPs of ten or fewer amino acids as lead antibacterial molecules ........................... 6 Tryptophan- and arginine-rich short antimicrobial peptides (TARAMPs). ............................ 7 Proline-rich short antimicrobial peptides (PRAMPs)............................................................ 13 Ultrashort antimicrobial peptides. ......................................................................................... 19 1.6. Peptidomimetic approaches................................................................................................ 21 1.7. Short AMP-based peptidomimetics in clinical trials.......................................................... 25 1.8. Conclusion .......................................................................................................................... 28 1.9. References .......................................................................................................................... 28 1.10. Concluding remarks ......................................................................................................... 47 Chapter 2: Challenges in developing therapeutic agents targeting Gram-negative bacteria ....... 48 2.1. Introductory remarks .......................................................................................................... 48 2.2. Contributions of authors ..................................................................................................... 48 2.3. Drug resistance drives the development of new antibiotics
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