Staphylococcus aureus DNA gyrase: mechanism and drug targeting

Chung, Terence (2012) Staphylococcus aureus DNA gyrase: mechanism and drug targeting. Doctoral thesis, University of East Anglia.

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Increases in Staphylococcus aureus resistance against existing treatment options and the shortage of new antibiotics signals an urgent need for new treatments for the ongoing battle against the development of antibiotic resistance.
DNA gyrase is an essential bacterial type II DNA topoisomerase that manipulates DNA topology by performing transient double-strand breaks and DNA strand passage. As gyrase is vital for bacterial survival, it is an effective antibacterial target. By understanding the mechanistic differences between S. aureus gyrase and the better studied Escherichia coli counterpart, we aim to better utilise S. aureus gyrase as an antibacterial target and improve the design of future antibacterial drug.
This study has investigated features unique to S. aureus DNA gyrase: the potassium glutamate (KGlu) salt-dependent and salt-specific supercoiling. This KGlu dependency in S. aureus, but not E. coli gyrase, was partially attributed to the differences in the Cterminal
domain of the gyrase A-subunit (GyrA). The discovery of the two novel monovalent alkali metal cation (M+) binding sites located in N-terminal domain of GyrB by protein crystallography has suggested a novel role of these M+ ions in the supercoiling functions of DNA gyrase, providing theoretical links to the unique KGlu dependency in S. aureus gyrase and the dependency of monovalent ions in E. coli and B.subtilis gyrase.
Diospyrin, a phyto-naphthoquinone, was found to be active against S. aureus in vivo. It inhibits S. aureus gyrase and topo IV in vitro, with gyrase as the preferred target. Further studies suggested the binding site of Diospyrin to be located in the N-terminal domain of GyrB. Diospyrin also partially inhibits the ATPase activity of GyrB in an
allosteric manner. Diospyrin is hypothesized to bind to a novel binding site between the ATPase domain and the transducer domain. Diospyrin also inhibits both the
relaxation and the DNA cleavage ability of gyrase, suggesting it inhibits gyrase with a novel mechanism.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Users 2593 not found.
Date Deposited: 14 Sep 2015 13:44
Last Modified: 14 Sep 2015 13:44


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