| Summary: | <p>β-Lactams, which inhibit bacterial transpeptidases, are currently the most widely used antibacterials globally. The emergence of bacterial resistance, conferred by β- lactamases in particular, which degrade β-lactam antibiotics, poses a perilous threat to human health. In conjunction with the development of β-lactamase inhibitors (BLIs), new antibiotics are needed that are stable to β-lactamase degradation. As β- lactamases provide bacterial resistance against β-lactam-containing antibiotics, the development of non-β-lactam transpeptidases inhibitors may be a promising strategy.</p>
<p>Chapter 1 provides a review of non-β-lactam analogues synthesised as potential antibacterial inhibitors, from which several promising molecular scaffolds such as the lactivicins and the benzisothiazolinones were identified. Chapter 2 describes the design and synthesis of non-β-lactam analogues using both reported and novel synthetic methodologies. In Chapter 3, synthesised compounds were evaluated for antibacterial and inhibitory activity against transpeptidases produced by Mycobacterium tuberculosis. In Chapter 4, synthetic methods for the modification of 2- oxoglutarate (2-OG), originally conceived for the synthesis of γ-lactone-functionalised lactivicin analogues, were repurposed for the synthesis of 2-OG analogues as inhibitors of isocitrate dehydrogenase (IDH) variants. In response to the coronavirus pandemic, Chapter 5 details the development of benzisothiazolinones as inhibitors of SARS-CoV-2 main protease.</p>
<p>The work described in this thesis made substantial progress in developing strategies for the synthesis of non-β-lactam transpeptidase inhibitors, which will be used to combat antimicrobial resistance, and pioneered facile methodology for the synthesis of functionalised 2-OG analogues for biological studies.</p>
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