Investigation of bioactive scaffolds as antimicrobials

The increasing incidence and prevalence of antibiotic-resistant bacterial strains is a worrying global issue. Since the ‘Golden Age’ of antibiotic drug discovery, identifying compound classes with distinct mechanisms of action has proved to be a difficult task. An additional approach to overcoming antibacterial resistance is the identification of antibiotic adjuvants. When co-administered with an antibiotic, such compounds can restore the biological activity of an antibiotic towards a resistant bacterial strain. In the Copp group, ongoing studies have found that compounds containing a polyamine moiety can display intrinsic antibacterial activity and antibiotic potentiating abilities. The polyamine compounds are suspected of perturbing the cell membranes of bacteria, leading to either cell death or increased antibiotic susceptibility. Claramine A1, a known membrane disruptor, acted as a lead compound resulting in the synthesis of 42 novel polyamine compounds containing podocarpic acid as the core cyclic fragment. The extensive SAR study of polyamino-podocarpic acid derivatives identified the necessary scaffolds to elicit anti-MRSA, antifungal, and potentiating activity for this compound class. During an antimicrobial screening program of Copp-group compounds from previous projects, 1,5-disubstituted imidazoles and ascididemin scaffolds were identified as lead compounds, prompting further investigation. An SAR investigation of 1,5-disubstituted imidazoles afforded 71 novel second-generation 1,5-disubtsituted imidazole compounds. Biological evaluation of all 116 1,5-disubstituted imidazoles found that this class of compound exhibits specific biological activity against methicillin-resistant S. aureus. Computational studies identified key physicochemical properties within this set of compounds required for biological activity. Synthetic studies were conducted on the ascididemin scaffold to expand on the existing set of compounds. During derivatisation, an unexpected but welcome outcome produced two new carbon skeletons for this compound class. These were the tetrahydroquinoline and N-methyl tetrahydroquinoline variants, which have not been synthesised before. The identification of these gives an opportunity further to explore the potential antimicrobial activity of ascididemin derivatives.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Chemistry

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2022

Author dc:creator

• Li, Steven Aaron

Advisors dc:contributor.advisor

• Copp, Brent R.
• Cadelis, Melissa M.

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/60781

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/60781