Chemical Synthesis of Novel Calcium-Dependent Lipopeptide Antibiotics

Antibacterial resistance represents one of the greatest challenges facing humanity. Infections caused by untreatable multi-drug resistant pathogens continue to rise resulting in as many as 700,000 deaths per year worldwide. Antimicrobial peptides (AMPs) have emerged as a rich yet underexplored source of novel antibiotics and include clinically important polymyxins and vancomycin used for the treatment of multi-drug resistant (MDR) infections. An important class of AMPs are calcium-dependent lipopeptide antibiotics (CDLAs) of which daptomycin is the only novel antibiotic introduced for clinical use in the last 20 years. Recently, metagenomic mining emerged as a novel platform for discovery of clinically relevant natural products delivering two examples of novel sub-classes of CDLAs, the malacidins and the cadasides. This thesis describes synthetic strategies towards malacidin A and cadaside B utilising solid-phase peptide synthesis (SPPS). Chapter 1 gives an introduction to the problem of antibacterial resistance and an overview of clinically relevant AMPs and AMPs discovered in recent years. A summary of SPPS techniques is also provided. Chapter 2 gives an overview of CDLAs and their reported chemical syntheses. Chapter 3 describes a versatile and concise synthetic strategy towards the malacidin A scaffold demonstrated by preparation of six simplified analogues with variation in the lipid component and one diastereomeric analogue of malacidin A. The cyclic core of the malacidin A analogues was accessed via in-solution macrocyclization of a side-chain protected linear precursor obtained by Fmoc-SPPS with a late-stage lipidation. Despite the lack of activity of the prepared analogues, the synthetic strategy reported herein can be easily applied to the straightforward generation of further analogues in order to explore the structure-activity relationship (SAR) of this important CDLA. Chapter 4 describes investigations towards the total synthesis of cadaside B. The synthetic strategy towards this cyclic lipodespsipeptide was first established by preparation of a simplified analogue with the key steps involving on-resin esterification of a lipidated linear peptide precursor and in-solution macrocyclization. The preparation of a simplified analogue enabled the side-reactions of diketopiperazine-driven depsipeptide bond cleavage and epimerization upon installation of the dipeptide building block to be addressed. Application of this synthetic strategy towards the native sequence of cadaside B generated the desired peptide albeit in low yield. 1D and 2D 1H NMR analyses of the synthetic cadaside B indicated significant deviations compared to the natural product suggesting a different structure of the synthesized peptide. Further structural analyses and antibacterial testing are currently being undertaken for comprehensive characterisation of synthetic cadaside B.

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

2021

Author dc:creator

• Kovalenko, Nadiia

Advisors dc:contributor.advisor

• Brimble, Dame Margaret
• Harris, Paul

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/2292/62181

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/62181