The synthesis and determination of the antibacterial properties of targeted antibacterial agents

There is currently a great need to develop new antibacterial compounds, not only for the treatment of bacterial infections, but also for use in microbial growth media for the selective isolation and detection of pathogenic bacteria. It is known that the expression of glycosidase enzymes within bacteria is unequally distributed and these differences in profiles have been widely utilised for the detection and differentiation of pathogenic bacteria using chromogenic and fluorogenic glycosides. In this research this differential enzyme expression is utilised in order to develop targeted antibacterial compounds. This programme builds on previous work where it was observed that the coupling of l-R-aminoethylphosphonic acid, a known antibacterial compound, to galactose, afforded an antibacterial p-galactoside where activity could be directly correlated to the p-galactosidase expression of the test organisms. Thus, this research firstly explores the glycosidic derivatisation oftriclosan (a broad spectrum antibacterial). As such, the successful synthesis of eight triclosan-u/li-Dcglycopyranoside derivatives is reported, employing a number of synthetic strategies, including neighbouring group participation and thermodynamic control. This allowed access to either a- or p- linked glycosides of a range of carbohydrates. The determination of the minimum inhibitory concentration (MIC 100) values of seven of the synthesised triclosan-c/Belr-glycopyranosides in two types of broth (DM4 and Nutrient Broth No. 2) as well as in Nutrient Agar is subsequently reported. It was found that the formulation of the medium had a significant effect on the potency of the triclosan-c/p-Dsglycopyranosides compounds, with MIClOO values being significantly lower in Nutrient Broth No. 2 than DM4. The discrepancy in values was subsequently attributed to the presence of horse serum in DM4. The correlation between the antibacterial activity of the triclosan-c/jf-Dvglycopyranosides and the glycosidase expression as determined by chromogen hydrolysis was not always achieved. It was postulated this was due to substantial differences in rates of hydrolysis, rate of uptake and the detection limits between the two. The modification of l-R-aminoethylphosphonic acid (AEP) at the amino group was also examined to determine whether these derivatives were more active than the parent compound, and with a view to further glycosylation reactions. The synthesis of five analogues of AEP was successfully achieved. The MIClOO values of these compounds were determined against a small panel of organisms. Results showed that none of the analogous compounds displayed any antibacterial activity, with no significant improvements over AEP being observed.EThOS - Electronic Theses Online ServiceGBUnited Kingdo