Thesis--Auburn University, 2008. / Abstract. Vita. Includes bibliographical references (p. 85-90).

Thesis (Ph.D.)--University of Wollonong, 2005. / Typescript. Includes bibliographical references: leaf 206-219.

Thesis (M. Sc.), Memorial University of Newfoundland, 1998. / Restricted until June 1999. Bibliography: leaves 104-110.

Thesis (PhD) - Environment and Biotechnology Centre, Faculty of Life and Social Sciences, Swinburne University of Technology, 2008. / Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Environment and Biotechnology Centre, Faculty of Life and Social Sciences, Swinburne University of Technology - 2008. Typescript. "July 2008". Includes bibliographical references (p. 317-336).

Thesis (Ph.D.)--University of Waikato, 2010. / Title from PDF cover (viewed July 30, 2010). Includes bibliographical references (p. 214-261)

No description available.

Potassium ions are the most abundant cation and potassium transport is essential in maintaining cellular homeostasis through the regulation of cell turgor and cytoplasmic pH. It allows bacteria to grow and survive, therefore, the potassium pool needs to be strictly controlled, which is mainly performed by transport systems that contain a KTN domain. The potassium efflux system, Kef, is such a KTN-bearing system and it is widespread among Gram negative bacteria. The system provides protection against harmful electrophiles through cytoplasmic acidification. Kef is a glutathione-regulated protein: it is inhibited by glutathione (GSH), but it becomes activated by binding glutathione-S-conjugates (GSX), that are formed in the presence of electrophiles. GSH or GSX are bound in the same pocket that is located in a cytosolic regulatory domain which controls the K+ flux. Previous studies already showed that bacterial growth is inhibited when the gating of Kef is manipulated, which makes Kef a potential target for developing novel antibacterial drugs. Structure-Function studies have already lead to a better understanding of the regulation of potassium efflux activity, but no quantitative analyses had been performed until now. A simplified model Kef system (SdKef) is presented and a novel assay was developed that provided new insights into the structural components necessary for the gating of Kef. This assay makes the search for modulators of Kef, and therefore potential novel antibacterial drugs, more easily accessible. Another objective was to identify the nucleotide(s) bound and to determine its role in controlling the Kef system. This nucleotide was identified as AMP which is essential for stability of the Kef system.

Cyclic dipeptides (CDPs) are amino acid-based compounds, some of which possess antibacterial activity. The encapsulation of certain drugs into liposomes has been found to improve their activity in terms of bioavailability and duration of action. Liposomes are small vesicles that are under investigation as drug carriers for the delivery of therapeutic agents. A number of liposome formulations are currently under clinical trial review, whilst some have already been approved for clinical use. The aim of this study was to optimize a liposomal cyclo(Tyr-Pro) formulation and to assess its antibacterial activity against various Gram-positive and Gram-negative bacteria. Response surface methodology (RSM) using the central composite design (CCD) model was used to optimize liposomal formulations of cyclo(Tyr-Pro) for each of the four bacteria, namely Bacillus cereus, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Percent drug encapsulated and bacterial inhibition were investigated with respect to two independent variables, i.e. lipid composition and cholesterol content. Design Expert 8 was used for the purpose of finding the combination of independent variables that would yield an optimal formulation for each bacterium. The model selected by the software failed to adequately correlate the predicted models to the experimental data. The in vitro experiments showed that the antibacterial activity of liposome-encapsulated cyclo(Tyr-Pro) was superior to that of its free counterpart. Binding maximum or Bmax for the encapsulated compound at concentrations as low as 0.412 mg/ml, was significantly higher than that obtained for free cyclo(Tyr-Pro) which was tested at a concentration of 20 mg/ml. Furthermore, encapsulation of cyclo(Tyr-Pro) into a liposome formulation enhanced its potency. This was evident in the lower IC50 values for the liposomal compound when compared to free cyclo(Tyr-Pro).

The in vitro activity of twelve cephalosporins (first generation: Cephalothin, Cefazolin; second generation: Cefoxitin, Cefamandole, Cefuroxime, Cedonicid; third generation: Ceftazidime, Ceftizoxime, Cefotaxime, Cefoperazone, Ceftriaxone, Moxalactam) were studied against 146 strains of Gram negative bacilli belonging to the following families: Enterobacteriaceae Proteus vulgarius (2), P. mirabilis (5), Providencia stuartti (6), P. alkalifaciens (5), Morganella morganii (16), Serratia marcescens (14), Enterobacter cloacae (17), E. aerogenes (9), Kluyvera ascorbata (3), Citrobacter freundii (14), C. diversus (3), C. amalonaticus (1), Yersinia intermedia (1), Y. enterocolitica (2); Pseudomonadaceae: Pseudomonas aeruginosa (31), P. fluorescens (3); Neisseriacaee: Acinetobacter anitratus (3), Acinetobacter lwoffi (1); and Vibrionaceae: Aeromonas hydrophilia (4), Plesiomonas shigelloides (1), Campylobacter jejuni (5)). This investigation, which studied the activity of all the mentioned cephalosporins against each strain, suggests that resistance to the third generation cephalosporins has already emerged in such species as S. marcescens, E. cloacae, E. aerogenes, C. freundii, P. aeruginosa, P. fluorescens, A. anitratus, A. lwoffi, and Campylobacter jejuni. This resistance is most pronounced in Enterobacter spp., Serratia marcescens, and Pseudomonas aeruginosa. The second generation cephalosporins, particularly Cefoxitin and perhaps Cefuroxime, are chief inducers of resistance in Enterobacter and Serratia. In the pseudomonads difference mechanisms seem to operate than those taking place in Enterobacter-Serratia. The study also shows that resistance is not a generic characteristic in Proteus, Providencia, or Citrobacter but rather specific. Some aspects of mechanisms of resistance to cephalosporins are discussed. Concern is here indicated that at least in certain groups of bacteria, the use of the second generation cephalosporins may lead to emergence of resistance to the third generation group.

No description available.