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Bioactive secondary metabolites from bacteria. Natural products from marine and terrestrial bacteria, dereplication, isolation and investigation of bacterial secondary metabolites

dc.contributor.advisorEspen, Hansen
dc.contributor.authorSchneider, Yannik Karl-Heinz
dc.date.accessioned2020-09-08T22:05:26Z
dc.date.available2020-09-08T22:05:26Z
dc.date.issued2020-09-29
dc.description.abstractThe thesis gives an introduction to natural product drug discovery and the underlying chemical principles that make natural products privileged structures for drug discovery. Paper I deals with the isolation of Lipid 430 from cultures of two <i>Algibacter</i> sp. isolates and the investigation of their anti-proliferative and anti-bacterial effect. Paper II describes the isolation of Serratiochelin A and C and investigation of the specific anti-bacterial and anti-proliferative effect of the siderophore Serratiochelin A. Paper III deals with the isolation of new Suomilides from a <i>Nostoc</i> sp. isolate and the investigation of their bioactivity. In addition, it proposes a biosynthetic pathway for Banyaside/Suomilide like molecules and their characteristic azabicyclononane moiety.en_US
dc.description.doctoraltypeph.d.en_US
dc.description.popularabstractThe present thesis deals with the isolation, identification and investigation of natural products from marine and terrestrial bacteria. Natural products are molecules produced by living organisms and natural product discovery, particularly using bacteria, is a promising strategy to discover new bioactive molecules and drug-candidates. Natural products were the source for a big share of drugs that enabled modern pharmacotherapy. Examples for that are the over-the-counter drug aspirin or lifesaving antibiotics that are present in your daily life, which are in use now for many decades until today. Other natural product based drugs, like cyclosporine, enabled transplantation medicine as we know it and methylergometrine saved, and still saves, uncounted lives of young mothers. From its historical roots, natural product chemistry became a scientific discipline where chemists and pharmacists isolated active molecules and started to modify them chemically, in order to get stronger effects, less side effects and molecules that were easier to obtain by synthesis. After the discovery of the first antibiotics, microorganisms, such as bacteria and fungi, became subject to screening programs that successfully led to the discovery of immunosuppressants, antibiotics and chemotherapeutics. The last 30 years led to further insights in the properties that make natural products suitable drug candidates, which motivates to further investigate them in order to find better cancer medication and new antibiotics, effective against upcoming pathogens with antibiotic resistance. Bacteria are continuing to be a great source for new chemical entities and new drug candidates. Starting with fifteen isolates from the Arctic Ocean, two isolates of the genus Algibacter were found to have antimicrobial bioactivity. Mass-spectrometric analysis of the extracts lead to the identification of one common metabolite that was isolated. Its structure was solved via NMR and found to be lipid 430. From a co-culture of two bacteria, the siderophore serratiochelin A was isolated and its anti-cancer effect as well as its specific anti-microbial effect on Staphylococcus aureus were discovered. Investigation of the hydrolysed degradation product serraticohelin C revealed that the latter had no bioactivity raising the question if the bioactivity of serratiochelin A is caused by a specific effect instead of iron deprivation since both compounds are chelating Fe(III). The investigation of a Nostoc sp. isolate led to the isolation of suomilide A and three new suomilides (B-D). Those highly modified glyco-peptides have been subject to previous synthetic approaches but their bioactivity was unknown. We were able to assign their potential biosynthetic cluster and to investigate their bioactivity. They showed no anti-bacterial or anti-biofilm effect and no toxicity towards human cell lines. The biological role and function of those complex cyanobacterial metabolites are still unknown.en_US
dc.description.sponsorshipThis work received funding from the following projects: The Marie Skłodowska-Curie Action MarPipe of the European Union (grant agreement GA 721421 H2020-MSCA-ITN-2016) and from UiT – The Arctic University of Norway.en_US
dc.identifier.isbn978-82-8266-183-6
dc.identifier.urihttps://hdl.handle.net/10037/19264
dc.language.isoengen_US
dc.publisherUiT The Arctic University of Norwayen_US
dc.publisherUiT Norges arktiske universiteten_US
dc.relation.haspart<p>Paper I: Schneider, Y.K.-H., Hansen, K.Ø., Isaksson, J., Ullsten, S., Hansen E.H. & Andersen, J.H. (2019). Anti-Bacterial Effect and Cytotoxicity Assessment of Lipid 430 Isolated from <i>Algibacter</i> sp. <i>Molecules, 24</i>(21), 3991. Also available in Munin at <a href=https://hdl.handle.net/10037/16686>https://hdl.handle.net/10037/16686</a>. <p>Paper II: Schneider, Y., Jenssen, M., Isaksson, J., Hansen, K.Ø., Andersen, J.H. & Hansen, E.H. (2020). Bioactivity of Serratiochelin A, a Siderophore Isolated from a Co-Culture of <i>Serratia</i> sp. and <i>Shewanella</i> sp. <i>Microorganisms, 8</i>, 1042. Also available in Munin at <a href=https://hdl.handle.net/10037/19078>https://hdl.handle.net/10037/19078</a>. <p>Paper III: Schneider, Y.K.-H., Liaimer, A., Isaksson, J., Hansen, K.Ø., Andersen, J.H. & Hansen, E.H. New suomilides isolated from <i>Nostoc</i> sp. KVJ20, bioactivity and biosynthesis. (Manuscript).en_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/721421/EU/Improving the flow in the pipeline of the next generation of marine biodiscovery scientists/MarPipe/en_US
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2020 The Author(s)
dc.rights.urihttps://creativecommons.org/licenses/by-nc-sa/4.0en_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)en_US
dc.subjectVDP::Mathematics and natural science: 400::Chemistry: 440::Analytical chemistry: 445en_US
dc.subjectVDP::Matematikk og Naturvitenskap: 400::Kjemi: 440::Analytisk kjemi: 445en_US
dc.subjectVDP::Mathematics and natural science: 400::Chemistry: 440::Pharmaceutical chemistry: 448en_US
dc.subjectVDP::Matematikk og Naturvitenskap: 400::Kjemi: 440::Legemiddelkjemi: 448en_US
dc.subjectVDP::Mathematics and natural science: 400::Basic biosciences: 470::Biochemistry: 476en_US
dc.subjectVDP::Matematikk og Naturvitenskap: 400::Basale biofag: 470::Biokjemi: 476en_US
dc.titleBioactive secondary metabolites from bacteria. Natural products from marine and terrestrial bacteria, dereplication, isolation and investigation of bacterial secondary metabolitesen_US
dc.typeDoctoral thesisen_US
dc.typeDoktorgradsavhandlingen_US


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