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Hwang, Hee-Jong

University of British Columbia

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.

Text

2022-07-22

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/82195

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/