Combination Therapy Using Synthetic Antimicrobial Polymers: a Platform to Combat Multidrug-Resistant Bacteria Rashin Namivandi Z
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Combination Therapy Using Synthetic Antimicrobial Polymers: A Platform to Combat Multidrug-Resistant Bacteria Rashin Namivandi Zangeneh A thesis in fulfilment of the requirements for the degree of Doctor of Philosophy School of Chemical Engineering Faculty of Engineering April 2020 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Namivandi Zangeneh First name: Rashin Other name/s: Abbreviation for degree as given in the University calendar: PhD School: School of Chemical Engineering Faculty: Faculty of Engineering Title: Combination Therapy Using Synthetic Antimicrobial Polymers: A Platform to Combat Multidrug-Resistant Bacteria Abstract 350 words maximum: The widespread failure of antibiotics in the treatment of multidrug-resistant (MDR) or biofilm-associated infections is a critical global healthcare issue. Thus, there is an urgent need for the development of novel and effective antimicrobial agents or strategies. This dissertation explores the use of a potent synthetic antimicrobial polymer that consists of biocompatible oligo(ethylene glycol), hydrophobic ethylhexyl and cationic primary amine functional groups as a potential alternative to currently available antibiotics. In particular, this work investigates the advantages of combination therapy involving synthetic antimicrobial polymers and other antimicrobial agents as a novel therapeutic approach against bacterial infections. Firstly, a potent antibiofilm agent was developed by incorporating NO donor moieties into the structure of the synthetic antimicrobial polymer. The NO-loaded polymer showed dual-action capability as it could release NO to disperse biofilm, while the polymer caused membrane disruption. A synergistic effect in biofilm dispersal, planktonic and biofilm killing activities was observed against the Gram-negative bacteria Pseudomonas aeruginosa (P. aeruginosa). In a second approach, synergistic combinations containing the synthetic antimicrobial polymer and two antibiotics, namely doxycycline and colistin, were developed. Coadministration of these compounds significantly improved the bacteriostatic efficacy against wild-type and MDR P. aeruginosa strains. In addition, the combination involving doxycycline showed synergistic bactericidal activity, could hinder resistance development in P. aeruginosa and was capable of reviving susceptibility to treatment in the resistant strains. In a third approach, synthetic antimicrobial polymers in the form of core-shell micelles were used in combination with antimicrobial essential oils, namely carvacrol and eugenol, where the antimicrobial polymeric micelles played a secondary role as delivery vehicles for essential oils. Coadministration of these compounds led to significant biofilm inhibition and synergistic killing effects against wild-type and MDR P. aeruginosa strains. Finally, a structure-activity relationship study was conducted to investigate the effect of polymer topology on biological performance. Linear copolymers with different chain lengths, block and hyperbranched copolymers were synthesized and assessed for antimicrobial and hemolytic activities. The best performing polymer in terms of biological properties was determined to have hyperbranched architecture and was >156 times more selective toward P. aeruginosa over red blood cells. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350-word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). ………………………………………… …………………………………….……… ……….……………………...…….… Signature Witness Signature Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: Page | ii Originality statement ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….............. Page | iii INCLUSION OF PUBLICATIONS STATEMENT UNSW is supportive of candidates publishing their research results during their candidature as detailed in the UNSW Thesis Examination Procedure. Publications can be used in their thesis in lieu of a Chapter if: The student contributed greater than 50% of the content in the publication and is the “primary author”, ie. the student was responsible primarily for the planning, execution and preparation of the work for publication The student has approval to include the publication in their thesis in lieu of a Chapter from their supervisor and Postgraduate Coordinator. The publication is not subject to any obligations or contractual agreements with a third party that would constrain its inclusion in the thesis Please indicate whether this thesis contains published material or not. This thesis contains no publications, either published or submitted for publication ☐ (if this box is checked, you may delete all the material on page 2) Some of the work described in this thesis has been published and it has been documented in the relevant Chapters with acknowledgement (if this box is ☒ checked, you may delete all the material on page 2) This thesis has publications (either published or submitted for publication) ☐ incorporated into it in lieu of a chapter and the details are presented below CANDIDATE’S DECLARATION I declare that: I have complied with the Thesis Examination Procedure where I have used a publication in lieu of a Chapter, the listed publication(s) below meet(s) the requirements to be included in the thesis. Name Signature Date (dd/mm/yy) Page | iv Copyright statement ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation. Signed…………………………… Date……………………………… Authenticity statement ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format. Signed…………………………… Date……………………………… Page | v Acknowledgements First and foremost, my most profound appreciation and gratitude go to my supervisor, Prof. Cyrille Boyer, for his invaluable support, patience and mentorship throughout my PhD. Also, my sincere thanks to my co-supervisor, Dr. Edgar Wong, for his tremendous guidance that has been instrumental in my academic development. Without them, none of this would have been possible. I would like to acknowledge the University of New South Wales and the Australian Government for providing me with the scholarship that enabled me to perform my studies in one of the high-ranking universities in the world; this has been greatly effective on my personal and career development. I would like to thank my masters and honours thesis students, Rebecca J Kwan, Maeva Sauvage-Nguyen, and Yiling Yang, for their contributions and help throughout the projects. Special thanks to Prof. Naresh Kumar, Dr. Kitty Ho, Prof. Mark Duncan Willcox and Dr. Debarun Dutta, for their helpful advice and contributions. My sincere thanks go to Eh Hau Pan and Camillo Taraborrelli for their invaluable efforts in managing the laboratories and for their help and support throughout my time in UNSW. To all my PhD mates and friends: Zahra Sadrearhami, Parisa Moazzam,