Chemical and biological studies on thiopeptide antibiotics : total synthesis of micrococcin P2 and synthetic efforts towards lactocillin
department or school: Science, Faculty of
department or school: Chemistry, Department of
data provider: DSpace
degree campus: UBCV
creator: Hwang, Hee-Jong
issued: 2022-07-22T21:54:08Z
issued: 2022
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: The World Health Organization (WHO) describes antimicrobial resistance (AMR) as one of the three greatest threats to human health. Yet, the current global antibiotic pipeline is scarce, and new resources to combat bacterial pathogens that have become resistant to available antibiotics are few and far between. Therefore, the development of new antibiotics is urgently needed to address the ongoing “antibiotic crisis”. In that regard, thiopeptide antibiotics appear to be good potential sources of new antibacterials. They are potent inhibitors of bacterial protein synthesis and their mode of action is reasonably well understood. Yet, little effort has been made to clinically leverage these natural products. In part, this may be due to the fact that there existed no viable synthetic methods to conduct medicinal chemistry work on these substances. This dissertation presents the first total synthesis of micrococcin P2, a D-series, 26-membered antibiotic, by a synthetic route that incorporates a number of refinements relative to past approaches, and that provides access to large quantities of end product. The synthesis demonstrates economical, concise, efficient, convergent, and diversity-oriented protocols that facilitate medicinal chemistry ventures to a considerable extent. This has enabled an extensive biological evaluation of micrococcin P2 and congeners against Clostridioides difficile, Mycobacterium tuberculosis and non-tuberculous Mycobacterium (NTM). A parallel effort demonstrates the application of the new methodology in a synthetic study toward lactocillin, a metabolite of the human symbiotic bacterium, Lactobacillus gasseri. The work presented herein outlines a route to the most advanced synthetic precursor of lactocillin described to date.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/82195
note: Chemical and Biological Studies on Thiopeptide Antibiotics: Total Synthesis of Micrococcin P2 and Synthetic Efforts towards Lactocillin by Hee-Jong Hwang B. Sc., The University of British Columbia, 2012 M. Sc., The University of British Columbia, 2015 A DISSERTATION 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) July 2022 ⓒ Hee-Jong Hwang, 2022 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 Biological Studies on Thiopeptide Antibiotics: Total Synthesis of Micrococcin P2 and Synthetic Efforts towards Lactocillin” submitted by Hee-Jong Hwang in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry Examining Committee: Marco A. Ciufolini, Professor, Department of Chemistry, UBC Supervisor Stephen Withers, Professor, Department of Chemistry, UBC Supervisory Committee Member David Perrin, Professor, Department of Chemistry, UBC Supervisory Committee Member Katherine S. Ryan, Associate Professor, Department of Chemistry, UBC University Examiner Yossef Av-Gay, Professor, Department of Medicine, UBC University Examiner Additional Supervisory Committee Members: Jason Hein, Associate Professor, Department of Chemistry, UBC Supervisory Committee Member iii Abstract The World Health Organization (WHO) describes antimicrobial resistance (AMR) as one of the three greatest threats to human health. Yet, the current global antibiotic pipeline is scarce, and new resources to combat bacterial pathogens that have become resistant to available antibiotics are few and far between. Therefore, the development of new antibiotics is urgently needed to address the ongoing “antibiotic crisis”. In that regard, thiopeptide antibiotics appear to be good potential sources of …
has type: Thesis/Dissertation
date issued: 2022-11
is shown at: 10.14288/1.0416339
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: Ciufolini, Marco A.
type: Text
identifier URI: http://hdl.handle.net/2429/82195