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Fatty Acids and Monoglycerides As Novel Prophylaxis Against Gonococcal Ophthalmia Neonatorum

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Fatty Acids and Monoglycerides As Novel Prophylaxis Against Gonococcal Ophthalmia Neonatorum Fatty acids and monoglycerides as novel prophylaxis against gonococcal ophthalmia neonatorum Colin Peter CHURCHWARD This thesis is being submitted in partial fulfilment of the requirements of Kingston University for the award of Doctor of Philosophy Nov 2016 Abstract Neonates born to mothers with an active gonorrhoea infection can develop serious sight threatening eye infections. The causative agent, Neisseria gonorrhoeae, is passed to the neonate during birth, and infects the eyes of the neonate. The condition, ophthalmia neonatorum, develops 0-14 days after birth and initially presents as a painful inflammation of the eye with yellowish purulent discharge from one or both eyes. One preventative action used by some countries is the use of an ophthalmic prophylaxis which is usually an ophthalmic ointment which contains an antibiotic. This its self can cause chemical conjunctivitis. This study evaluates the potential to use a fatty acid or fatty acid derivative as the active antimicrobial agent in an ophthalmic prophylaxis. A panel of thirty-seven initial candidates were screened for anti-gonococcal properties. Seven of this panel were selected and tested against for ocular irritation potential using in vitro models and anti-gonococcal properties tested further in simulated tear fluid. Finally a single candidate, monocaprin, was selected as the main drug candidate. Ophthalmic formulations of liquid and semi-solid dosage forms were made and evaluated. Liquid dosage forms performed the best in in vitro tested and were further evaluated in cell culture and explanted models. The cell culture model suggested that monocaprin could be used to prevent infection 90 minutes after the cell were inoculated with the bacteria. An explanted corneal infection model was used to assess the potential formulations. It was shown that the anti- gonococcal properties of the drug candidate were inhibited on the ocular surface but this this could be countered by increasing the amount of monocaprin in the formulation. The formulations containing 0.188 % and 0.25 % (w/w) monocaprin were in some cases able to totally clear inoculations of higher cell numbers on the surface of the eye. Passage on agar plates containing monocaprin showed that increasing resistance due to genomic mutation is not likely and that existing mechanisms of fatty acid resistance did not give cross- resistance to monocaprin. However, duplicate samples passaged on monocaprin both acquired identical mutations in the dksA gene which may confer a small decrease in susceptibility. Also, work done on the processing of natural sources of fatty acids showed that treatment of coconut oil by use of a purified lipase or a lipase secreting yeast produced powerful anti-gonococcal substances. This could has the potential to be used in developing nations treat gonococcal and other bacterial infection. Overall, the work in thesis demonstrates that there is potential in the use a fatty acid or fatty acid derivative, most likely monocaprin, to be used as the active antimicrobial agent in an ophthalmic ii prophylaxis but more evaluation in terms of in vivo testing is required to demonstrate that the higher levels of monocaprin do not cause irritation to the eye. iii Name of Candidate: COLIN PETER CHURCHWARD Student ID No: 1464824 Degree for which dissertation/thesis being submitted: PhD I declare that while registered for a research degree at Kingston University, I have not been a registered candidate or enrolled student for another award at any other academic or professional institution I declare that no material contained in the thesis has been used in any other submission for an academic award. I declare that all material contained in the thesis is my own original work, and that any references to or use of other sources have been clearly acknowledged within the text. Signature of Candidate: Date: Colin Churchward 25/11/2016 iv Acknowledgement Firstly I would like to thank Sparks (registered charity number: 1003825) for the funding of consumables and my post at Kingston University through grants 11KIN01 and 13KIN01. Without this support the research within this thesis could not have taken place. I would like to thank my primary supervisor Dr Lori Snyder who originally thought of the concept of the main aim of this project and for her support and guidance throughout. I would also like to thank my second supervisor Prof. Raid Alany who spent many hours in meetings teaching the principals of pharmaceutics to a microbiologist. During the three year of this work I had help from many others. The main bulk of the scientific work was done in the microbiology research laboratory, 2105. The Laboratory Director, Prof. Mark Fielder and Laboratory Manager, Dr. Simon Gould were supportive throughout my time there. As were numerous PhD students and post-doctorates placed there during my time, in particular fellow Neisseria researchers Dr. Ruth Griffin and Miss Sabrina Roberts. I need to thank others for technical assistance; Dr. Hamdy Abdelkader and Dr. Ali Al-Kinani assisted with formulation work in particular the choice of viscosity enhancers and Dr. Julian Swindon for assistance with the HPLC development and validation. I was also helped by Dr. Ruth Kirk who showed me how to process samples for histology and taught me how to use the fluorescence microscope. I was also assisted by Prof. Tony Walker who advised on which fluorescent labels to use in my work. I would also like to thank the BSc project students who I have worked with on this project. Miss Polliane Arruda and Mr. Andrew Sears aided with testing of natural produces; Miss Anna Tran who assisted with early work on cell infection studies; and Mr. Alan Calder who did the passage work on fatty acid containing media. I would also like to thank Public Health England who supplied clinical gonococcal strains free of charge. Finally, I would like to thank my partner Sarah Crouch who has supported through this project and write-up period. She has supported me both financially and emotionally. v Table of Contents Abstract …………………………………………………………………………………………………… i Declaration …………………………………………..………………………………….……………… iv Acknowledgements ………………………………………………………………………………… v List of figures ………………………………………………………………………………….………. xii List of tables ………..………………………………………………………………………….…..…. xv List of abbreviations ………………………………………………………………………....…… xvii Chapter 1 - Introduction................................................................................................ 1 1.1 Neisseria gonorrhoeae and its diseases ........................................................................... 2 1.1.1 History of gonorrhoea ........................................................................................................ 2 1.1.2 Ophthalmia neonatorum and its history ........................................................................... 3 1.1.3 Ophthalmia neonatorum prophylaxis in the antibiotic age ............................................... 6 1.1.4 Neisseria gonorrhoeae ....................................................................................................... 7 1.1.5 Gonorrhoea and other N. gonorrhoeae infections .......................................................... 10 1.1.6 Prevalence and incident rates of gonorrhoea ................................................................. 11 1.1.7 Antimicrobial resistance .................................................................................................. 16 1.1.8 Control measures of ophthalmia neonatorum ................................................................ 19 1.1.9 Virulence factors .............................................................................................................. 22 1.1.10 Attachment and internalisation ..................................................................................... 22 1.1.11 Efflux pumps .................................................................................................................. 25 1.2 Fatty acids and other novel solutions to antimicrobial resistance ................................... 27 1.2.1 Antimicrobial agents discovery ........................................................................................ 27 1.2.2 Fatty acids ........................................................................................................................ 28 1.2.3 Lipid nomenclature systems ............................................................................................ 29 1.2.4 Antimicrobial effects of fatty acids .................................................................................. 32 1.2.5 Mechanism of action of fatty acids and monoglycerides ................................................ 32 1.2.6 Inhibition of antimicrobial properties .............................................................................. 33 1.3 Anatomy of the eye and ophthalmic formulations ......................................................... 36 1.3.1 Structure and function ..................................................................................................... 36 1.3.2 The sclera and cornea ...................................................................................................... 39 1.3.3 Lacrimation and other defence mechanisms ................................................................... 39 1.3.4 Types of ophthalmic dosage forms .................................................................................. 44 1.3.5 Traditional liquid dosage forms ......................................................................................
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