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Phd Thesis ZHANG Kaixi.Pdf This document is downloaded from DR‑NTU (https://dr.ntu.edu.sg) Nanyang Technological University, Singapore. Glycosylated cationic block co‑beta‑peptide as antimicrobial and anti‑biofilm agents against Gram‑positive bacteria Zhang, Kaixi 2019 Zhang, K. (2019). Glycosylated cationic block co‑beta‑peptide as antimicrobial and anti‑biofilm agents against Gram‑positive bacteria. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/137037 https://doi.org/10.32657/10356/137037 This work is licensed under a Creative Commons Attribution‑NonCommercial 4.0 International License (CC BY‑NC 4.0). Downloaded on 11 Oct 2021 00:27:16 SGT GLYCOSYLATED CATIONIC BLOCK CO-BETA-PEPTIDE AS ANTIMICROBIAL AND ANTI-BIOFILM AGENTS AGAINST GRAM- POSITIVE BACTERIA ZHANG KAIXI Interdisciplinary Graduate School HealthTech NTU 2019 Sample of first page in hard bound thesis I Glycosylated cationic block co-beta-peptide as antimicrobial and anti-biofilm agents against Gram-positive bacteria ZHANG KAIXI Interdisciplinary Graduate School HealthTech NTU A thesis submitted to the Nanyang Technological University in partial fulfillment of the requirement for the degree of Doctor of Philosophy 2019 i Statement of Originality I hereby certify that the work embodied in this thesis is the result of original research, is free of plagiarised materials, and has not been submitted for a higher degree to any other University or Institution. 18 Dec 2019 Date ZHANG KAIXI ii Supervisor Declaration Statement I have reviewed the content and presentation style of this thesis and declare it is free of plagiarism and of sufficient grammatical clarity to be examined. To the best of my knowledge, the research and writing are those of the candidate except as acknowledged in the Author Attribution Statement. I confirm that the investigations were conducted in accord with the ethics policies and integrity standards of Nanyang Technological University and that the research data are presented honestly and without prejudice. 18 Dec 2019 Date Assoc Prof Kevin Pethe Prof Chan Bee Eng, Mary iii Authorship Attribution Statement This thesis contains material from 1 paper(s) published in the following peer- reviewed journal(s) where I was the first author. Chapter 4 and 5 is published as Kaixi Zhang, Yu Du, Zhangyong Si, Yang Liu, Michelle E. Turvey, Cheerlavancha Raju, Damien Keogh, Lin Ruan, Subramanion L. Jothy, Reghu Sheethal, Kalisvar Marimuthu, Partha Pratim De, Oon Tek Ng, Yonggui Robin Chi, Jinghua Ren, Kam C. Tam, Xue-Wei Liu, Hongwei Duan, Yabin Zhu, Yuguang Mu, Paula T. Hammond, Guillermo C. Bazan, Kevin Pethe*, Mary B. Chan-Park*, Enantiomeric glycosylated cationic block co-beta-peptides eradicate Staphylococcus aureus biofilm and antibiotic- tolerant persisters, Nature Communications 10, 4792 (2019) doi:10.1038/s41467-019-12702-8 The contributions of the co-authors are as follows: • Prof Mary Chan and Prof Kevin Pethe supervised and guided the overall research. • I prepared the manuscript drafts. The manuscript was revised by Prof Mary Chan and Prof Kevin Pethe. • I conducted the in vitro tests with Sheethal Reghu and Ruan Lin for the biofilm tests. • I conducted the in vivo acute wound infection model with Dr Jo Thy Subramanion and Dr Damien Keogh. • I conducted the ex vivo human skin experiment with Dr Michelle Turvey. • I conducted all the rest in vitro and in vivo tests. iv • Dr Du Yu, Si Zhangyong and Dr Cheerlavancha Raju synthesized the polymers. I conducted the MALDI-TOF and GPC measurements. • Dr Liu Yang and Prof Mu Yuguang conducted the computer simulation. • Prof Mary Chan and Prof Guillermo Bazan guided chemical synthesis. • Prof Ren Jinghua and Prof Zhu Yabin supervised in vivo toxicity tests. • Prof K.C. Tam guided the solution property study and the DLS tests. • Dr Kalisvar Marimuthu, Dr Partha Pratim De and Dr Oon Tek Ng isolated and provided strains from local hospital TTSH and provided useful suggestions. • Prof Duan Hongwei, Prof Liu Xuewei, Prof Robin Chi and Prof Paula Hammond participated in the supervision of the project. 18 Dec 2019 Date Zhang Kaixi v Acknowledgement I would like to express my sincere gratitude to my supervisor, Professor Mary Chan Bee Eng from School of Chemical and Biomedical Engineering, who has given her wholehearted support to supervise me on this project. I am truly grateful for the tremendous exposures and opportunities that she has provided for me. I also would like to thank my supervisor, Assoc Prof Kevin Pethe from Lee Kong Chian School of Medicine, who has given munificent support and valuable scientific insights to my research. I would also like to thank Assoc Prof Duan Hongwei, Assoc Prof Liu Xue Wei, Prof Tan Choon Hong, Asst Prof Sanjay Chotirmall and Assoc Prof Andrew Tan Nguan Soon, for meaningful discussions and guidance. I would like to express my deepest appreciation to the research fellows, Dr Du Yu, Dr Moon Tay Yue Feng, Dr Jo Thy Lachumy Subramanion, Dr Li Peng, Dr Raju Cheerlavancha, Ms Ruan Lin, Ms Sheethal Reghu for their tremendous support and their wealth of knowledge that greatly contributed to this project. I would also express my gratitude to my teammates and colleagues, Mr Si Zhangyong, Mr Hou Zheng, Mr Zhong Wenbin, Mr Wu Yang, Mr Yeo Chun Kiat, Mr He Jingxi, Mr Zhang Penghui, Mr Li Jianghua, Ms Wang Liping for their encouragement and generous support in my research. Special thanks to my husband and my family, who deeply inspired me in every aspect of my pursuits. Last but not least, I would like to reserve special praise to Interdisciplinary Graduate School (IGS) and HealthTech NTU for the funding and platform they provided. This gives me valuable opportunity for truly integrated and meaningful research. vi Table of Contents Abstract .................................................................................................................................... 1 Chapter 1 Introduction and literature review ...................................................................... 3 Section 1.1 Overview of antimicrobial resistance (AMR) .................................................... 3 Section 1.2 Aims and objectives ........................................................................................... 5 Section 1.3 Literature review ................................................................................................ 7 Section 1.4 Motivation and approach to design a novel co-beta-peptide ............................ 38 Chapter 2: Experimental materials and procedures .......................................................... 40 Section 2.1 Materials and equipment .................................................................................. 40 Section 2.2 Synthetic procedures ........................................................................................ 41 Section 2.3 Biological tests ................................................................................................. 47 Chapter 3 Synthesis and characterization of the enantiomeric glycosylated cationic block co(beta-peptides) ......................................................................................................... 67 Section 3.1 Synthesis of the (co)polymers via one-shot one-pot AROP ............................. 67 Section 3.2 Molecular weight characterization of the polymer series ................................. 85 Section 3.3 Solution properties of the polymer series ......................................................... 88 Chapter 4 Antibacterial properties and mechanism of action study of the glycosylated cationic block co(beta-peptides) ........................................................................................... 95 Section 4.1 In vitro biocompatibility ................................................................................... 96 Section 4.2 Minimal Inhibitory concentration (MIC) of (co)polymer series ...................... 99 Section 4.3 Kill kinetics of the copolymer PDGu(7)-b-PBLK(13) ................................... 103 Section 4.4 Bacterial resistance development towards copolymer .................................... 104 Section 4.5 Mechanism of Action (MoA) study................................................................ 108 Chapter 5 Block co(beta-peptides) eradicate antibiotic-tolerant persisters and biofilm in vitro and in vivo .................................................................................................................... 128 Section 5.1 In vitro persister eradication ........................................................................... 130 Section 5.2 MRSA biofilm bacteria eradication and biomass dispersal ............................ 134 Section 5.3 Broad-spectrum Gram-positive bacteria biofilm dispersal ............................. 145 Section 5.4 In vivo biocompatibility and antimicrobial properties .................................... 149 Chapter 6 Conclusions and future directions ................................................................... 160 Section 6.1 Conclusions .................................................................................................... 160 Section 6.2 Future directions ............................................................................................. 161 vii List of Figures Figure 1-1 Definition of antibiotic (a) resistance, (b) tolerance and (c) persistence...................15 Figure 1-2 Molecular pathways underlying persistence in E. coli..............................................17 Figure 1-3 Antibiotic persistence
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