Award details

Molecular characterisation of the FtsK DNA motor and its interaction with topo IV in chromosome segregation

Reference	BB/D01882X/1
Principal Investigator / Supervisor	Professor Larry Mark Fisher
Co-Investigators / Co-Supervisors
Institution	St George's University of London
Department	Basic Medical Sciences
Funding type	Research
Value (£)	250,921
Status	Completed
Type	Research Grant
Start date	01/04/2006
End date	31/03/2009
Duration	36 months

Abstract

FtsK is a DNA motor protein that acts at the bacterial septum to coordinate chromosome segregation and cell division. FtsK activates topo IV, the chromosome decatenase, and target of quinolone drugs used against Streptococcus pneumoniae and other Gram-positives. Antipneumococcal quinolones stabilise a DNA cleavage complex of topo IV that is converted into a lethal lesion by DNA replication and other tracking processes on DNA. We aim to understand the mechanisms by which the DNA motor domain of pneumococcal FtsK directs topo IV functions. These studies will provide important new insights on the role of FtsK-topo IV interactions in chromosome segregation and quinolone action relevant to the design of new antibacterials.

Summary

FtsK is a multifunctional enzyme with the key role of coupling bacterial chromosome segregation and cell division. It is fixed to the DNA septum, a ring structure separating daughter cells, and functions as an ATP-driven DNA motor to pump chromosomal DNA through the closing septal ring. Moreover, it interacts with topo IV, an enzyme that separates topologically interlocked chromosomes and whose activity is blocked by quinolone drugs. These agents are widely used to treat infections caused by Streptococcus pneumoniae and other Gram-positive pathogens. Quinolones trap a topo IV-DNA complex that is converted into a lethal double stranded DNA break by motor proteins that track on DNA. Despite its fundamental scientific and pharmaceutical importance, little is known about topo IV, its interactions with FtsK and quinolones. By using a soluble truncated FtsK protein that retains the DNA motor activity, we aim to study how pneumococcal FtsK directs and modulates topo IV and its targeting by quinolones. The work will lead to significant advances in our understanding of chromosome segregation and cell division, and how antimicrobial quinolones disrupt these processes. In the longer term, the work should aid the development of more effective antibacterials.

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	Microbiology, Pharmaceuticals
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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