Total Synthesis of Naturally Occurring Antimicrobial Peptides

This thesis describes the first total synthesis of naturally occurring lanthipeptide tikitericin, as well as its N-terminal truncated analogues. The thesis also explores the total chemical synthesis of the lipopeptide antibiotic daptomycin and analogues along with evaluation of their antibacterial activity. Tikitericin is a newly described lanthipeptide characterized by four intramolecular thioether linked (methyl)lanthionine bridges. It was isolated from the New Zealand extremophilic microorganism Thermogemmatispora strain T81, collected at Tikitere (Hell’s Gate), Rotorua. However, the chemical and biological properties of tikitericin haven’t been established due to the limited amount of natural product isolated. This thesis describes the first total synthesis of tikitericin via Fmoc-solid-phase peptide synthesis (SPPS). The key noncanonical (methyl)lanthionine residues were synthesized in solution phase via an improved synthetic route and subsequently assembled to construct the peptide backbone using Fmoc-SPPS. N-Terminal truncated analogues of tikitericin were also prepared in order to evaluate the contribution of each sequential ring of the polycyclic lanthipeptide to the antibacterial activity. Daptomycin is a cyclic lipodepsipeptide natural product, exhibiting potent antimicrobial activity against highly resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and several species of Streptococci. Previous chemoenzymatic synthesis, semi-synthesis, and combinatorial biosynthesis only produced a very limited number of daptomycin analogues, leaving much of the chemical space unexplored. A de novo solid-phase synthesis of daptomycin via Boc chemistry was achieved. The challenging ester bond formation between the nonproteinogenic amino acid kynurenine was achieved by esterification of a threonine residue with a protected tryptophan. Subsequent late-stage on-resin ozonolysis, inspired by the biomimetic pathway, afforded the kynurenine residue directly. Synthetic daptomycin possessed potent antimicrobial activity against S. aureus, while five other daptomycin analogues containing (2R,3R)-3-methylglutamic acid, (2S,4S)-4-methylglutamic acid or canonical glutamic acid at position twelve prepared using this new methodology were all inactive; clearly establishing that the (2S,3R)-3-methylglutamic acid plays a key role in the antimicrobial activity of daptomycin.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Chemical Sciences

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2019

Author dc:creator

• Xu, Buzhe

Advisors dc:contributor.advisor

• Brimble, MA
• Harris, P

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.

Licence dc:rights.uri

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

Handle dc:identifier.uri

https://hdl.handle.net/2292/50137

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/50137