Highly infectious pathogenic strains of bacteria are becoming increasingly resistant to the current clinical antibiotics which have created a dire need for the development of novel antibiotics. O-Acetylpeptidoglycan esterase 1 (Ape1) is a periplasmic esterase present in several peptidoglycan (PG) O-acetylating pathogenic species of Gram-positive and all Gram-negative bacteria that perform this modification to this essential cell wall polymer. Inhibition of this growth-limiting enzyme may prove the principle that Ape1 has the potential to be the target for the development of a novel class of antibiotics. Ape1 plays a crucial role in bacterial growth by regulating PG turnover through catalytic removal of the C-6 acetyl group from O-acetylPG. This activity is required for the continued metabolism of PG because the major autolytic enzymes involved, the lytic transglycosylases, require a free C-6 hydroxyl group to produce their reaction product, 1,6-anhydromuramic acid. Several of the compounds that have been identified to effectively inhibit Ape1, were re-evaluated by determining their kinetic parameters. Work presented in this thesis explored the inhibitory potential of these compounds, belonging to the anthraquinone (alizarin, quinizarin, quinalizarin, emodin, sennoside A) or tannin (ellagic acid) families of compounds, both in vitro and in vivo, among species of bacteria that are known to O-acetylate their PG. Of the inhibitory compounds tested, ellagic acid was found to be most effective in vitro, with an IC50 value of 0.91 µM ± 0.06, Ki 1.18 ± 0.04 and in vivo it was shown to reduce bacterial growth.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OGU.10214/5256 |
| Date | 08 January 2013 |
| Creators | Zia, Asad |
| Contributors | Clarke, Anthony J. |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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