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dc.contributor.authorHawkins, Paige M. E.
dc.date.accessioned2020-08-06
dc.date.available2020-08-06
dc.date.issued2020en_AU
dc.identifier.urihttps://hdl.handle.net/2123/23010
dc.description.abstractNatural products are a rich source of bioactive molecules that have been harnessed as therapeutics for millennia. In our current climate, natural products still remain the predominant source of novel drug inspiration. The process of developing drug leads from natural products delves into the chemical-biology interface, often requiring the culmination of total synthesis, to provide synthetic access to the compound, and subsequent rational activity-guided drug design. As a result of the rapidly escalating antibiotic-resistance crisis, the demand for new antibiotics has never been greater. As such, the work within this thesis describes the development towards natural product-inspired drug leads as novel antimicrobial leads. Chapter 2 describes the total synthesis of ecumicin and ohmyungsamycin A, cyclic depsipeptide natural products with potent antimycobacterial activity. The synthesis entails the preparation of two non-proteinogenic amino acids and incorporation of these into the assembly of the linear peptide via a solid-phase peptide synthesis methodology. This includes a key on-resin esterification and dimethylation, followed by a late-stage, conformationally-guided solution-phase macrolactamization. These peptides were evaluated for their antimycobacterial activity. Chapter 3 describes the generation of synthetic analogues based upon the ecumicin and ohmyungsamycin A natural products. Several synthetic routes were investigated with the aim of improving the ease, efficiency, and reliability of the synthesis. In this way, three generations of analogues were synthesized and evaluated in vitro against Mtb. Lead analogues were then further explored in a range of biological assays and a chimeric analogue, incorporating the optimal features of each generation of analogues was synthesized and evaluated. Chapter 4 describes attempts to minimize the ecumicin and ohmyungsamycin A natural product pharmacophore and, in the process, valuable ClpC1 small molecule binders were discovered. The binding of a rationally-designed small analogue library was also investigated with the aim of introducing a linker for the purposes of synthesizing bacterial proteolysis targeting chimeras (Bac-PROTACs). Chapter 5 describes the synthesis of the aromatic peptide desmethoxycoralmycin A and the coralmycin A natural product, which possesses potent activity against Gram-negative and Gram positive bacteria. A two-directional solid-phase synthesis strategy was employed, including a key three-step O-acylation, O to N shift, and O-alkylation to incorporate the unusual 2,3-dihydroxy-para-aminobenzoic acids. Assembly of these peptides also involved the design and synthesis of a suitably protected 2,3-dihydroxy-para-aminobenzoic acid and the non-proteinogenic amino acid, erythro-β-methoxy-L-aspartic acid.en_AU
dc.language.isoenen_AU
dc.publisherUniversity of Sydneyen_AU
dc.subjectTuberculosisen_AU
dc.subjecttotal synthesisen_AU
dc.subjectnatural productsen_AU
dc.subjectpeptidesen_AU
dc.subjectsolid-phase synthesisen_AU
dc.subjectGram-negativeen_AU
dc.titleTotal synthesis and beyond: Developing drug leads to combat antibiotic resistanceen_AU
dc.typeThesis
dc.type.thesisDoctor of Philosophyen_AU
dc.rights.otherThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en_AU
usyd.facultySeS faculties schools::Faculty of Science::School of Chemistryen_AU
usyd.degreeDoctor of Philosophy Ph.D.en_AU
usyd.awardinginstThe University of Sydneyen_AU
usyd.advisorPayne, Richard


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