Bacterial DNA gyrase and Topoisomerase IV (Gyrase/Topo IV)

Bacterial DNA gyrase and topoisomerase IV are essential type II topoisomerases that manage the topological state of DNA during replication and transcription (Nature Reviews Microbiology, 2007). DNA gyrase is unique to bacteria and is responsible for introducing negative supercoils into the DNA, which facilitates the unwinding of the double helix (PubMed, 2014). Topoisomerase IV plays a critical role in decatenating or unlinking daughter chromosomes after DNA replication is complete (StatPearls, 2023). These enzymes are heterotetrameric, consisting of two different subunits: GyrA and GyrB for gyrase, and ParC and ParE for topoisomerase IV (UniProt, 2024). Because they are indispensable for bacterial cell division and differ structurally from human topoisomerases, they serve as primary targets for several classes of antibiotics (Nature Reviews Microbiology, 2007). Fluoroquinolones, the most prominent class of drugs targeting these enzymes, work by stabilizing the covalent DNA-enzyme complex, preventing the religation of DNA strands (StatPearls, 2023). This action results in the accumulation of double-strand breaks, which triggers cell death. Resistance to these agents is a significant clinical challenge, often mediated by mutations in the genes encoding the enzyme subunits or by increased drug efflux (PubMed, 2014).

Other names

Microbial type II topoisomerasesDNA gyraseTopoisomerase IVGyrA/GyrBParC/ParEDNA topoisomerase (ATP-hydrolyzing)

Fluoroquinolones bind to the enzyme-DNA complex to stabilize the cleavage complex, preventing DNA religation and causing lethal double-strand DNA breaks (StatPearls, 2023). Aminocoumarins like novobiocin competitively inhibit the ATPase activity of the GyrB subunit, preventing the energy-dependent supercoiling of DNA (Nature Reviews Microbiology, 2007).