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Novel Antibacterial Biomaterials and Polymers Based on Quorum Sensing Inhibitors

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Novel Antibacterial Biomaterials and Polymers Based on Quorum Sensing Inhibitors NOVEL ANTIBACTERIAL BIOMATERIALS AND POLYMERS BASED ON QUORUM SENSING INHIBITORS A thesis submitted in fulfilment of the degree of Doctor of Philosophy By Aditi Taunk Supervisors Prof. Naresh Kumar Prof. Mark D.P. Willcox Prof. David StC. Black School of Chemistry The University of New South Wales Kensington, Australia December 2017 This thesis is dedicated to my beloved mother, Dr. Archana Taunk for her unconditional love & support and for always believing in me! THE UNIVERSITY OF NEW SOUTH WALES Thesis/DissertationSheet Surname or Family name: TAUNK Firsi name: ADITI Other name/s: Abbreviation for degree as given in the Universitycalendar: PhD Faculty: Science School: School of Chemistry Title: Novel Antibacterial Biomaterials and Polymers Based on Quorum Sensing Inhibitors ABSTRACT Bacterial biofilms on life-saving implanted medical devices are a serious problem in long-term. At present, no effective strategies are available and the emergence of multi-drug resistance has highlighted the need to develop novel antibacterial coatings to combat device- related infections. One approach is to block the bacterial communication pathway or quorum sensing (QS), which is responsible for biofilm formation, by incorporating QS inhibitors (QSls) such as dihydropyrrolones (DHPs) and furanones (FUs) on biomaterial surfaces and polymers. The endogenous biological signalling molecule nitric oxide (NO) is also a potential candidate for prevention of biomedical infections due to its antibiofilm activity. In this study, DHPs and brominated FUs were immobilized on surfaces via a non-specific nitrene-insertion method. The successful covalent attachment of compounds was confirmed by X-ray photoelectron spectroscopy. The coated surfaces showed excellent in vitro activity against Staphylococcus aureus and Pseudomonas aeruginosa. Interestingly, DHP surfaces at low concentrations (0.17-0.35 % halogen) were found to display similar levels of activity as FUs with higher surface attachment (0.41-0.74 % Br), which was possibly due to change in orientation of DHP during attachment. The influence of DHP orientation and absence of an exocyclic double bond on the biological activity was then examined by specific covalent attachment using EDC/NHS coupling. The orientation of DHP with free lactam ring exposed to bacterial medium showed higher activity compared to DHPs attached from the nitrogen of the lactam ring. In addition, DHPs lacking the exocyclic double bond were also able to reduce bacterial adhesion without killing both strains of bacteria, indicating DHPs retained their activity even in absence of the exocyclic bond. This project also focused on developing dual-action surfaces and polymers that were functionalized by DHPs via Michael-addition reaction and diazeniumdiolates (NO donors) derived from the reaction of secondary amines with NO gas. The DHP+NO surfaces demonstrated significantly higher efficacy in reducing colonization of both bacterial strains than the DHP coatings alone, while the hybrid polymer displayed excellent activity by inhibiting 95 % of P. aeruginosa biofilm at all concentrations (42-1 µM) via a non-toxic mechanism. Therefore, the coatings based on QSls show great potential in reducing device-related infections. 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 Universitylibraries 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: CERTIFICATE OF ORIGINALITY ‘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 material which to a substantial extent has 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 ...……………………………………........ i 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 …………………………………………… ii ABSTRACT Bacterial biofilms on life-saving implanted medical devices are a serious problem in long-term. At present, no effective strategies are available and the emergence of multi- drug resistance has highlighted the need to develop novel antibacterial coatings to combat device-related infections. One approach is to block the bacterial communication pathway or quorum sensing (QS), which is responsible for biofilm formation, by incorporating QS inhibitors (QSIs) such as dihydropyrrolones (DHPs) and furanones (FUs) on biomaterial surfaces and polymers. The endogenous biological signalling molecule nitric oxide (NO) is also a potential candidate for prevention of biomedical infections due to its antibiofilm activity. In this study, DHPs and brominated FUs were immobilized on surfaces via a non- specific nitrene-insertion method. The successful covalent attachment of compounds was confirmed by X-ray photoelectron spectroscopy. The coated surfaces showed excellent in vitro activity against Staphylococcus aureus and Pseudomonas aeruginosa. Interestingly, DHP surfaces at low concentrations (0.17–0.35 % halogen) were found to display similar levels of activity as FUs with higher surface attachment (0.41–0.74 % Br), which was possibly due to change in orientation of DHP during attachment. The influence of DHP orientation and absence of an exocyclic double bond on the biological activity was then examined by specific covalent attachment using EDC/NHS coupling. The orientation of DHP with free lactam ring exposed to bacterial medium showed higher activity compared to DHPs attached from the nitrogen of the lactam ring. In addition, DHPs lacking the exocyclic double bond were also able to reduce bacterial iii adhesion without killing both strains of bacteria, indicating DHPs retained their activity even in absence of the exocyclic bond. This project also focused on developing dual-action surfaces and polymers that were functionalized by DHPs via Michael-addition reaction and diazeniumdiolates (NO donors) derived from the reaction of secondary amines with NO gas. The DHP+NO surfaces demonstrated significantly higher efficacy in reducing colonization of both bacterial strains than the DHP coatings alone, while the hybrid polymer displayed excellent activity by inhibiting 95 % of P. aeruginosa biofilm at all concentrations (42– 1 µM) via a non-toxic mechanism. Therefore, the coatings based on QSIs show great potential in reducing device-related infections. iv ACKNOWLEDGEMENTS I would like to take this opportunity and thank everyone without whom this thesis would not have been written and to whom I am greatly indebted. First and foremost, I would like to express my sincere gratitude to my supervisor Prof. Naresh Kumar for the constant support, patience, motivation and immeasurable intellectual input throughout my PhD. Thank you for encouraging and guiding me with all the invaluable suggestions at all times. I could not have
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