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Title: An exploration of bacterial cell division using novel, drug-like inhibitors of FtsZ
Author: Adams, David William
ISNI:       0000 0004 2744 8243
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2011
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Cell division in almost all bacteria is orchestrated by the essential tubulin homologue FtsZ, which assembles into a ring-like structure and acts as a scaffold for the division machinery. Bacterial cell division was recently validated as an important target for new antibiotics by the demonstration that low molecular weight inhibitors of FtsZ, called benzamides, can cure mice infected with a lethal dose of Staphylococcus aureus. In order to understand the mode of action of the benzamides, a detailed cytological and biochemical analysis of their effects on cell division has been performed in the Gram-positive model organisms, Bacillus subtilis and S. aureus. In treated cells of B. subtilis FtsZ assembles into foci throughout the cell, including abnormal locations at the cell poles and over the nucleoid. These foci are not inactive aggregates as they remain dynamic, turning over almost as rapidly as untreated polymers. Remarkably, although division is completely blocked, the foci efficiently recruit division proteins that normally eo-assemble with FtsZ. However, they show no affinity for components of the Min or Nucleoid Occlusion systems, which normally act to spatially restrict FtsZ assembly. In vitro, the benzamides strongly promote the polymerisation of FtsZ, into hyper-stable polymers, which are highly curved. Importantly, even at low concentrations, benzamides transform the structure of the Z ring, resulting in abnormal helical cell division events. Furthermore, the characterisation of compound resistant mutants, and the isolation of a benzamide-dependent strain of B. subtilis, has revealed novel insights into the nature of Z ring assembly and the likely mechanisms by which the benzamides may act. Finally, the Nucleoid Occlusion factor Noc, which is a potent inhibitor of cell division, has been characterised in vitro and its ability to interact with, and modulate the assembly of FtsZ, examined.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available