Antibiotic reistance [sic] has become a major cause for concern in recent times and as such there is increased demand for new drugs that can obviate this issue. The vast majority of drugs exert their therapeutic effects by interfering with protein function; few drugs target the nucleic acid structures of DNA or RNA. Since these structures are underutilised as drug targets by comparison to proteins, it is desirable to design new antibiotics that target them. This allows new mechanisms of action to be explored and thus assists in circumventing the problem of antibiotic resistance. The Suckling group have been developing molecules that bind to the minor groove of DNA for many years and, when this PhD commenced, a panel of these were under preclinical investigation by an industrial collaborator. An investigation into the optimisation and scale up of these compounds will be discussed within this thesis. It will be revealed that one of the initial panel of lead compounds has been chosen to progress to Phase I clinical trials against both Clostridium Difficile and Methicillin-resistant Staphylococcus aureus (MRSA) and as such the investigation into suitable formulations will be discussed. Whilst a lead candidate had been selected this did not deter further investigation into minor groove binding compounds and this thesis also investigates modifications to these compounds that can lower affinity to the hERG ion channel, a major pharmaceutical anti-target. Whilst a range of our compounds display significant activity against Gram positive bacteria, very few have significant activity against Gram negative species. In order to investigate this, a series of compounds has been synthesised, based on known Gram negative active compounds, and these have been tested for activity against Pseudomonas aeruginosa. The proposed reason for the lack of activity, efficient cell efflux, was investigated by using an efflux pump inhibitor in the antibacterial assay and the results of this will be discussed. Very few drugs target RNA and because of this there is still much basic science to be learned about using RNA as drug target. This thesis has focused on obtaining more information on a recently discovered RNA element, known as a riboswitch, and their use as drug targets. In achieveing this two riboswitches have been selected to be investigated: the thiamine pyrophosphate riboswitch and the PreQ1 riboswitch. The suitability of each of these riboswitches as drug targets has been explored; however, in the case of the thiamine pyrophosphate riboswitch a set of novel modulators of this riboswitch have been prepared and shown by our collaborators to inhibit the growth of Gram negative bacteria. This is the first time that the TPP riboswitch has been shown to be a potential drug target.
|Date of Award||14 Jan 2013|
- University Of Strathclyde