Chemical and genetic investigations of marine and terrestrial bacteria towards bioactive natural product discovery
department or school: Science, Faculty of
department or school: Chemistry, Department of
data provider: DSpace
degree campus: UBCV
creator: Morgan, Kalindi Dasi
issued: 2021-05-13T23:20:38Z
issued: 2021
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: The discovery of novel natural products continues to be critical for the development of new pharmaceuticals. Innovative methods to discover novel natural products can reveal previously overlooked chemical diversity. One such method is genome mining, where sequenced bacterial genomes are assessed for the presence of biosynthetic gene clusters. Another such method is bioassay-guided fractionation. Following either of these approaches, the bacteria must be grown and harvested, and novel natural products must be isolated and characterized. In the first part of this thesis, a nitrogen-NMR guided approach was developed to retrieve genetically predicted natural products from bacterial cultures. Piperazic acid (Piz)-containing natural products were targeted because this unique amino acid is often found in peptidic natural products with biological activity and impressive chemical structures. Piz contains a unique nitrogen-proton NMR correlation targeted through ¹H-¹⁵N HSQC. The unique N-H correlation also gave access to Piz’s diagnostic spin system through ¹H-¹⁵N HSQC-TOCSY NMR experiments. These two ¹⁵N NMR experiments were used to monitor for the presence of peptides containing Piz in culture extracts of genome-mined bacteria. Through the application of these ¹⁵N NMR experiments to guide isolation of Piz natural products, four novel compounds were discovered from Streptomyces incarnatus NRRL 8089. Three of these were isolated and structure’s elucidated as part of this thesis work: dentigerumycin F (4.2), dentigerumycin G (4.1) and incarnatapeptin A (4.3). 4.3 demonstrated a unique bicyclic moiety not previously seen in chemical structures, and a fourth compound, incarnatapeptin B (4.4), has in vitro cytotoxicity. In the second part of the thesis, bioassay-guided fractionation is used to screen a small library of marine bacteria in various assays. Using this method, known natural product molecules were uncovered, along with the discovery of two novel natural products from t…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/78344
note: Chemical and Genetic Investigations of Marine and Terrestrial Bacteria towards Bioactive Natural Product Discovery by Kalindi Dasi Morgan B.Sc., The University of British Columbia, 2013 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) May 2021 © Kalindi Dasi Morgan, 2021 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Chemical and Genetic Investigations of Marine and Terrestrial Bacteria towards Bioactive Natural Product Discovery submitted by Kalindi Dasi Morgan in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry Examining Committee: Raymond Andersen, Professor, Joint appointment with Chemistry & Earth, Ocean and Atmospheric Sciences, UBC Co-supervisor Katherine Ryan, Associate Professor, Chemistry, UBC Co-supervisor Martin Tanner, Professor, Chemistry, UBC Supervisory Committee Member Andrew MacFarlane, Associate Professor, Chemistry, UBC University Examiner Reinhard Jetter, Professor, Joint appointment with Botany & Chemistry, UBC University Examiner Additional Supervisory Committee Members: Suzana Straus, Professor, Chemistry, UBC Supervisory Committee Member Harry Brumer, Professor, Joint appointment with Chemistry & Michael Smith Laboratories, UBC Supervisory Committee Member iii Abstract The discovery of novel natural products continues to be critical for the development of new pharmaceuticals. Innovative methods to discover novel natural products can reveal previously overlooked chemical diversity. One such method is genome mining, where sequenced bacterial genomes are assessed for the presence of biosynthetic gene clusters. Another such method is bioassay-guided fractionation. Following either of these approaches, the bacteria must be gro…
has type: Thesis/Dissertation
date issued: 2021-11
is shown at: 10.14288/1.0397473
language: eng
degree discipline: Chemistry
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Andersen, Raymond J.
contributor: Ryan, Katherine S.
type: Text
identifier URI: http://hdl.handle.net/2429/78344