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

FtsK是一种多功能酶，在细菌染色体分离和细胞分裂中起着关键的偶联作用。它固定在DNA隔膜上，这是一种分离子细胞的环状结构，作为atp驱动的DNA马达，将染色体DNA泵入闭合的隔膜环。此外，它与topo IV相互作用，topo IV是一种分离拓扑连锁染色体的酶，其活性被喹诺酮类药物阻断。这些药物广泛用于治疗由肺炎链球菌和其他革兰氏阳性病原体引起的感染。喹诺酮类药物捕获了一种拓扑IV-DNA复合物，这种复合物被跟踪DNA的运动蛋白转化为致命的双链DNA断裂。尽管topo IV具有重要的基础科学和药学意义，但人们对其与FtsK和喹诺酮类药物的相互作用知之甚少。通过使用保留DNA运动活性的可溶性截断FtsK蛋白，我们旨在研究肺炎球菌FtsK如何指导和调节topo IV及其喹诺酮类药物的靶向性。这项工作将导致我们对染色体分离和细胞分裂的理解取得重大进展，以及抗微生物喹诺酮类药物如何破坏这些过程。从长远来看，这项工作应该有助于开发更有效的抗菌药物。

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.