Topoisomerase IV (Topo IV) (Topo IV)

Topoisomerase IV is an essential bacterial enzyme belonging to the type II topoisomerase family, primarily responsible for the decatenation of interlinked daughter chromosomes following DNA replication (UniProt, 2023). It functions as a heterotetramer composed of two ParC and two ParE subunits, which work together to create transient double-strand breaks in DNA to allow the passage of another DNA duplex (PubMed, PMC3918213). This activity is crucial for ensuring successful chromosome segregation during bacterial cell division. Topoisomerase IV is a major therapeutic target for the fluoroquinolone class of antibiotics, particularly in Gram-positive pathogens like Staphylococcus aureus and Streptococcus pneumoniae (StatPearls, 2023). These drugs interact with the Topoisomerase IV–DNA complex by intercalating into the DNA at the cleavage site, effectively trapping the enzyme in a covalent intermediate state known as the "cleavage complex" (PubMed, PMC2746745). This stabilization prevents DNA re-ligation, leading to the formation of lethal double-strand breaks and subsequent bacterial cell death. Resistance to these agents often develops through point mutations in the quinolone resistance-determining regions (QRDR) of the ParC or ParE subunits, which reduce drug binding affinity (PubMed, PMC1193466). While highly effective, the use of drugs targeting this complex is associated with safety concerns such as tendonitis and potential central nervous system effects.

Other names

DNA topoisomerase IVParC-ParE complexTopoisomerase 4

Stabilization of the covalent enzyme-DNA cleavage complex, inhibition of DNA ligation, and induction of lethal double-strand DNA breaks (StatPearls, 2023).