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dc.contributor.advisorGoss, Rebecca J.
dc.contributor.authorZarins-Tutt, Joseph Scott
dc.description.abstractNatural product drug discovery has traditionally been the corner stone of medicine having provided cures to many of today’s most common diseases. In particular, antibiotics have revolutionised healthcare and extended human lifespan. However, since their introduction into the clinic, resistance to these drugs has arisen. With the number of new antibiotics being discovered in recent years declining, and fewer drugs making it past clinical trials, we have reached the point where antibiotic resistant infections have become common place and a serious threat to health and society. There is now an urgent requirement for the discovery of new antibiotics and in particular those with unexploited mode of action. This thesis details the different areas of natural product drug development from discovery through to analogue generation. In Chapter one, the history of natural products as therapeutics is explored with a particular focus on antibiotics and how resistance arises against these agents. It outlines why the discovery of new antibiotics is so important and new methods used to facilitate this search. Chapter two follows with the development of a screening platform for antibiotic induction, using the model Streptomyces; Streptomyces coleiolor M145. A variety of culture additives are explored for their ability to induce secondary metabolism production. Chapter three then details the sampling and identification of microbes from a pseudo-marine environment and their screening for their ability to produce secondary metabolites with antibiotic properties. The second half of this thesis centres on the non-ribosomal peptide echinomycin. Collaborators Aquapharm supplied the marine derived strain AQP-4895, capable of producing echinomycin. Chapter four details the establishment of AQP-4895 culturing conditions and the shift observed in production profile. Next Chapter five looks at producing echinomycin analogues through precursor directed biosynthesis. A range of halogenated quinoxaline carboxylic acids are synthesised and fed to AQP-4895, and the respective echinomycin analogues monitored by LC-MS. Chapter Six then aims to direct biosynthesis of the halogenated analogues, using mutasynthesis. Due to the lack of genetic data available surrounding the strain, an unusual approach was taken, using iPCR to create a template for homologous recombination.en_US
dc.publisherUniversity of St Andrews
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
dc.subjectNatural productsen_US
dc.subjectMarine bacteriaen_US
dc.subjectCryptic secondary metabolismen_US
dc.subject.lcshPharmaceutical microbiologyen_US
dc.subject.lcshMarine bacteriaen_US
dc.subject.lcshNatural productsen_US
dc.titleGene mining of biosynthesis genes and biosynthetic manipulation of marine bacteria for the production of new antibiotic candidatesen_US
dc.contributor.sponsorMedical Research Council (MRC)en_US
dc.type.qualificationnamePhD Doctor of Philosophyen_US
dc.publisher.institutionThe University of St Andrewsen_US
dc.rights.embargodatePrint and electronic copy restricted until 25th September 2020en_US
dc.rights.embargoreasonThesis restricted in accordance with University regulationsen_US

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Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted within the work, this item's licence for re-use is described as Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International