Development of New Antibiotics Based on Biotin Biology

Abstract

PARTIAL ABSTRACT: Biotin is an essential vitamin that is required for growth and pathogenicity of bacteria. Biotin protein ligase (BPL) catalyses the ordered reaction of biotin and ATP to give biotinyl-5̕´-MP, which then activates a number of biotin dependent enzymes that are critical to cell survival. Dethiobiotin synthase (DTBS) is the sole enzyme responsible for catalysing a key step in biotin biosynthesis, namely the carboxylation of 7,8-diaminopelargonic acid (DAPA), closing the ureido ring to form dethiobiotin in a reaction requiring a nucleotide triphosphate. Research undertaken in this thesis highlights strategies to selectively inhibit Staphylococcus aureus biotin protein ligase (SaBPL) using 1,2,3-triazole and sulfonamide isosteres to replace the phosphoroanhydride linker found in biotinyl-5´-AMP. In addition, this thesis discusses the design and development of inhibitors targeting Mycobacterium tuberculosis dethiobiotin synthase (MtbDTBS).