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

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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.