Molecular basis of DNA gating by topo IV and gyrase and its inhibition by antimicrobial drugs

点击翻译按钮获取中文摘要

Most life-forms whether humans, mammals, yeast or bacteria have a DNA genome. The DNA consists of two strands that wrap around each other to form the iconic DNA helix. During DNA replication, the helix must be unwound to allow copying and chromosome segregation. This process generates DNA supercoils and DNA tangles that can block replication. Topoisomerases solve the 'unwinding problem' by introducing transient single- or double-stranded breaks into DNA that dissipate supercoils and allow DNA synthesis to proceed. It is not surprising that topoisomerases are essential enzymes but they also turn out to be vital targets of antibacterial and anticancer drugs that inhibit cell growth. We aim to use biochemical and X-ray crystallographic approaches to study two bacterial topoisomerases called topo IV and gyrase. We wish to understand how these proteins act at the molecular level and how clinically important drugs such as fluoroquinolones target their functions. The work will focus on the well-characterised topo IV and gyrase from Streptococcus pneumoniae, a dangerous human pathogen that causes life-threatening pneumonia and meningitis. However the research has wider applications to other bacterial and microbial systems. Progress in this key area should aid development of new drugs that work against antibiotic-resistant organisms, a growing threat to our healthcare system.