Natural product guided antibacterial drug discovery: tetramates as core scaffolds

This thesis describes the synthesis and biological evaluation of a library of compounds containing the tetramic acid core in search of novel antibacterial drug candidates.
Chapter 1 discusses the need for new antibiotics due to the emergence of virulent bacterial strains resistant to clinically available drugs and the hiatus in the discovery of new replacement antibitoics that has become a global threat to human health. Different platforms for antibacterial drug discovery and the re-emergence of natural products-based approach that has gained importance in the quest for novel antibiotics are discussed. In this regard, the intrinsic antibacterial activity of natural products containing a tetramate core structure and the strategies developed to synthesise the core scaffold are described.
Chapter 2 discusses the use of ʟ-serine and ʟ-cysteine in tetramic acid synthesis and the application of ʟ-cysteine-derived thiazolidine templates suitable for stereoselective ring closing reactions to obtain the tetramic acid core with scope for further functionalization.
Chapters 3 and 4 describe a range of synthetic routes for appropriate substitutions of the tetramate core for compound library generation. Elaboration of the tetramate core via carboxamide tetramate synthesis, Suzuki-Miyaura cross-coupling reactions, glycosylations and their aglycone analogue synthesis, etherification, tetramate-pyroglutamate systems, Buchwald aminations/amidations, cycloadditions and β-lactam hybrids as possible chemical modifications of the tetramate core structure are discussed.
Chapter 5 describes the antibacetiral activity and physicochemical properties of the library of compounds synthesised. A preliminary evaluation of their antibiotic activity was conducted against S. aureus and E. coli using the hole-plate method. MICs of the tetramates synthesised were determined against several Gram-negative strains; Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Gram-positive strains; MRSA, Enterococcus faecalis and Streptococcus pneumoniae, in whole-cell bioassays. Physicochemical properties of the compound library were analysed to map the chemical space occupied by tetramates with potent antibacterial activity. Enzyme inhibition studies were conducted to identify possible modes of action that contribute to whole-cell antibiotic activity and in this regard, the inhibition of enzymes S. aureus topoisomerase IV, S. aureus RNA polymerase, E. coli RNA polymerase, E. coli gyrase and M. tuberculosis gyrase are discussed. Since plasma protein binding of compounds is an important factor that determines the bioavailability of antibiotics and their clinical outcome, a study of the binding affinity of these drug candidates to Human Serum Albumin (HSA) by both whole-cell bioassay and NMR spectroscopy-based protein binding experiments are discussed. Finally, a brief note on the potential of tetramic acids to function as proteasome inhibitors in anticancer chemotherapy is included at the end of this chapter.

Keywords: Natural product guided
Antibiotic drug discovery
Biology oriented synthesis
Tetramic acids
Advisor: Moloney, M