Development of targeted of antibacterial strategies of relevance to the food and pharma industries

With the modern climate of the 'super bugs', for example MRSA, and the ever-increasing resistance of bacteria to many of the traditional antibacterial treatments that are available, it is becoming more and more evident that new initiatives are needed to find alternative methods to treat bacterial infections. Although many approaches have been reported that make significant strides in this area, the ideal antibiotic remains elusive and further research is essential [1]. One of the strategies in the hunt for new treatments is to develop alternative and more effective uptake and release systems for delivering antibiotics to bacteria [2]. In this programme we propose to prepare a wide range of novel glycoside or peptide derivatives of existing antibiotics for the treatment of a range of bacterial infections of clinical importance. Antibiotics studied will be those that have shown promising antibacterial profiles in early studies, but whose full utility has not been fully exploited, for example due to their poor water solubility, or poor bacterial uptake properties [3]. In addition, the utility of the antibacterial agents developed to selectively recover pathogens from food or clinical samples that would normally be overgrown by the background flora will be explored. This will provide selective isolation media that do not suffer from the toxicity problems of existing media. In our approach it is hypothesised that linking the antibiotic to carbohydrates or peptides will produce water soluble agents that are actively taken into the bacterial cell via a carbohydrate or peptide permease uptake mechanism [4]. The agents themselves will be non-toxic to bacteria but once inside the cell, enzymes will selectively release the active antibiotic via hydrolysis of the glycoside or peptide linkage. Since different bacteria contain different glycosidase and peptidase enzymes it is envisaged that selective treatment can be effectively delivered by careful tailoring of the appropriate glycoside/peptide to the bacteria of interest. Once specific isomers have been prepared using current organic synthesis methods, biological analysis and bacteriological testing against a range of organisms will be performed. Thus, the student will have an opportunity to investigate the toxicity profiles of the derivatives in a range of cells using cell culture techniques, and will perform computational and physicochemical studies to determine the physicochemical parameters, stability and 'drug-like nature' of the materials of interest. Bacteriological testing to determine the specificity of action of the agents will include media development; exploring variations of amino acids, sugars, vitamins and other growth additives and enzyme inducers to achieve good growth of test organisms and optimum inhibition and selectivity. This project will provide training in a wide range of techniques including organic synthesis, carbohydrate chemistry, purification techniques and analytical chemistry. This will be coupled with the development of complementary skills to assess the antibacterial properties of the compounds, using enzymatic studies, HPLC, bacteriological testing and the development of appropriate media to support the growth of a range of bacteria. In addition, mathematical and computational expertise will be developed. [1] Su, Z. D., et al., Curr. Opin. Invest. Drugs, 2007, 8, 140 [2] Alanis, A. J., Archive. Med. Res, 2005, 36, 697 [3] Falagas, M.E., et al., Exp. Rev. Anti-infect. Ther., 2008, 6, 593 [4] Conners, S. B., et al., J. Bacteriol, 2005, 187, 7267