Antimicrobial metallohelices : discovery and mechanistic investigation

Chapter 1 outlines the potential of coordination and organometallic complexes in antimicrobial chemotherapy. Various historical examples are reviewed and their advantages and disadvantages discussed. Recent developments are then described, which have allowed the design of complexes with well-defined 3-dimensional structures, but in which the metal acts as a structural template rather than a reaction centre. Finally, consideration is given to the prospects for such compounds making a substantial contribution to the currently rather uncertain future of antimicrobial chemotherapy. Chapter 2 describes the discovery, synthesis and characterisation of new Class Ia (exo-pyridine) flexicates with varying ligand functionality, as well as some of the underlying challenges. The helicating effect of the linker connecting these bimetallic structures is subsequently explored, by investigating their structure, physical properties and aqueous stability. Chapter 3 focuses on the screening of water-soluble Class Ia flexicates for antimicrobial activity against various bacteria, allowing the establishment of lead compounds against Gram-negative bacteria. Various assays are then used in order to make further preclinical evaluations of the lead compounds and/or better understand the nature of the observed antimicrobial activity. For example, eukaryote toxicity and effect upon membrane integrity are assessed. Chapter 4 explores the use of tandem omics techniques (genomics, transcriptomics and proteomics) as means to develop credible hypotheses regarding the mechanism behind the potent activity of the lead compound against a pathogenic E. coli strain. The initial study describes the selection and characterisation of E. coli mutants tolerant the lead compound. Responses of the cell at the RNA and protein level respectively are then measured in response to the addition of the lead compound, at a sub-lethal dose. Chapter 5 Infers general conclusions from across this thesis and conveys suggestions for future work that may further expand this field. Chapter 6 details the experimental procedures used to carry out the work in this thesis. Appendix contains tables of crystallographic dat