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TARGETING MULTI-DRUG RESISTANT PATHOGENS with NOVEL ANTIMICROBIAL PEPTIDES Mohamed F

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TARGETING MULTI-DRUG RESISTANT PATHOGENS with NOVEL ANTIMICROBIAL PEPTIDES Mohamed F Purdue University Purdue e-Pubs Open Access Dissertations Theses and Dissertations January 2016 TARGETING MULTI-DRUG RESISTANT PATHOGENS WITH NOVEL ANTIMICROBIAL PEPTIDES Mohamed F. Mohamed Purdue University Follow this and additional works at: https://docs.lib.purdue.edu/open_access_dissertations Recommended Citation Mohamed, Mohamed F., "TARGETING MULTI-DRUG RESISTANT PATHOGENS WITH NOVEL ANTIMICROBIAL PEPTIDES" (2016). Open Access Dissertations. 1223. https://docs.lib.purdue.edu/open_access_dissertations/1223 This document has been made available through Purdue e-Pubs, a service of the Purdue University Libraries. Please contact [email protected] for additional information. TARGETING MULTI-DRUG RESISTANT PATHOGENS WITH NOVEL ANTIMICROBIAL PEPTIDES by Mohamed Fathy Kamel Mohamed A Dissertation Submitted to the Faculty of Purdue University In Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy Department of Comparative Pathobiology West Lafayette, Indiana December 2016 ii THE PURDUE UNIVERSITY GRADUATE SCHOOL STATEMENT OF DISSERTATION APPROVAL Dr. Mohamed N. Seleem Department of Comparative Pathobiology Dr. Lynn F. Guptill-Yoran Department of Comparative Pathobiology Dr. Ramesh Vemulapalli Department of Comparative Pathobiology Dr. Yoon Yeo Industrial and Physical Pharmacy Approved by: Dr. Suresh K. Mittal Head of the Departmental Graduate Program iii To my big family (my parents, brothers and sisters) and my small family (Somaia and Salma) for their endless love, support and encouragement iv ACKNOWLEDGMENTS First and foremost, I would like to thank Allah (God) for providing me the blessings and power to complete this work. I could never have done this without the faith I have in you. I would like to express my gratitude to my major advisor Dr. Mohamed Seleem for his guidance and support during my PhD. He encouraged me to be an independent researcher. He always pushed me hard to think outside the box and to work on new research avenues. He improved my poster and oral presentation skills. He also helps me to improve my writing and preparation of manuscripts. Aside from academia, he usually shares helpful advices about living abroad and how to enjoy our free times. I would also like to thank my committee members; Dr. Ramesh Vemulapalli, Dr. Lynn Guptill and Dr. Yoon Yeo for their feedback and suggestions. Dr. Ramesh Vemulapalli comments and suggestions after department seminars was so helpful to improve my research. Dr. Lynn Guptill provided me valuable comments on our project (Staphylococcus pseudintermedius). Dr. Yoon Yeo provided me valuable comments and technical support during our meetings on collaborative projects. I would like to express my gratitude to my professors in the department of bacteriology, immunology and mycology, Faculty of Veterinary Medicine, Beni-Suef University, Egypt. I would like to thank Dr. Fawzi R El-Seedy, Dr. Ismail Abd El- Hafeez Radwan Rahil, Dr. Walid Hamdi Hassan, Dr. Hala Hassan, Dr. Ahmed Abed, and Dr Amr Shehata for their help, encouragement and support. I thank all my past and current lab colleagues: Haroon Mohamed, Waleed Younis, Ahmed Hassan, Hassan Elsayed, Youssef Ahmed, Mostafa Abushahba, Maha Ahmed, Omar Ameen, Ahmed Omar, Ekramy Elsayed, Neha Debral, Manish Nebal, Anna Brezeden, Yihua Pei and Neha Argwal for their support and fun times. Special thanks to Haroon Mohamed for editing my manuscripts. Thanks to Barbara White for her support and guide during graduate school. v To my parents and my brothers and sisters, I am speechless! I can barely find the words to express all the wisdom, love and support you've given me. I thank my wife Somaia and my daughter Salma for their love, patience, emotional support and sacrifices. Finally, I would like to thank the Egyptian Ministry of Higher Education and the Egyptian Cultural and Educational Bureau (ECEB) for financial support of my graduate studies. vi TABLE OF CONTENTS LIST OF TABLES ............................................................................................................. ix LIST OF FIGURES ........................................................................................................... xi LIST OF ABBREVIATIONS .......................................................................................... xiv ABSTRACT ..................................................................................................................... xvi CHAPTER 1. LITERATURE REVIEW ......................................................................... 1 1.1 Introduction ............................................................................................................... 1 1.2 Mechanism of action of antimicrobial peptides ........................................................ 2 1.2.1 Cell membrane lysis ........................................................................................ 2 1.2.2 Non-permeabilizing mechanism (targeting intracellular components) ........... 3 1.2.2.1 Inhibition of cell wall synthesis .................................................................. 3 1.2.2.2 Inhibition of nucleic acid and protein synthesis: ........................................ 4 1.3 Advantages of Antimicrobial peptides ...................................................................... 5 1.3.1 Broad spectrum, rapid killing and synergism with antibiotics. ....................... 5 1.3.2 Active against drug resistant pathogens and low emergence of bacterial resistance to antimicrobial peptides ............................................................................. 6 1.3.3 Anti-endotoxic activity .................................................................................... 7 1.3.4 Immune-modulatory properties ....................................................................... 8 1.3.5 Wound healing properties ................................................................................ 9 1.3.6 Efficacy of peptides on established biofilms ................................................... 9 1.4 Limitations of antimicrobial peptides ..................................................................... 10 1.4.1 Potential for host toxicity ............................................................................... 10 1.4.2 Susceptibility to proteolytic digestion ........................................................... 12 1.4.3 Impaired antibacterial activity in the presence of physiologically relevant conditions (e.g., salts, acidic pH, plasma, and serum) ............................................... 13 1.4.4 Cost to manufacture ....................................................................................... 13 1.5 Antimicrobial peptides in clinical trials .................................................................. 14 1.6 References ............................................................................................................... 17 CHAPTER 2. TARGETING METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS WITH SHORT SALT-RESISTANT SYNTHETIC PEPTIDES...................... 33 vii 2.1 Abstract ................................................................................................................... 33 2.2 Introduction ............................................................................................................. 34 2.3 Materials and methods ............................................................................................ 35 2.4 Results ..................................................................................................................... 41 2.5 Discussion ............................................................................................................... 48 2.6 References ............................................................................................................... 52 CHAPTER 3. EFFICACY OF SHORT NOVEL ANTIMICROBIAL AND ANTI- INFLAMMATORY PEPTIDES IN A MOUSE MODEL OF METHICILLIN- RESISTANT STAPHYLOCOCCUS AUREUS (MRSA) SKIN INFECTION ................. 66 3.1 Abstract ................................................................................................................... 66 3.2 Introduction ............................................................................................................. 66 3.3 Materials and methods ............................................................................................ 67 3.4 Results and discussion ............................................................................................. 68 3.5 References ............................................................................................................... 71 CHAPTER 4. ANTIBACTERIAL ACTIVITY OF NOVEL CATIONIC PEPTIDES AGAINST CLINICAL ISOLATES OF MULTI-DRUG RESISTANT STAPHYLOCOCCUS PSEUDINTERMEDIUS FROM INFECTED DOGS ................... 75 4.1 Abstract ................................................................................................................... 75 4.2 Introduction ............................................................................................................. 76 4.3 Materials and methods ............................................................................................ 77 4.4 Results ..................................................................................................................... 82 4.5 Discussion ............................................................................................................... 85 4.6 References ..............................................................................................................
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