Bacterial DNA gyrase and topoisomerase IV cleaved DNA-enzyme complex (Gyrase-Topo IV-DNA complex)

The bacterial DNA gyrase and topoisomerase IV cleaved DNA-enzyme complex is a critical catalytic intermediate formed during the action of type II topoisomerases [1, 5]. DNA gyrase and topoisomerase IV are essential enzymes that manage the topological state of the bacterial genome; gyrase introduces negative supercoils to relieve torsional stress, while topoisomerase IV decatenates interlinked daughter chromosomes following replication [10, 13]. During their catalytic cycle, these enzymes create a transient double-strand break in DNA, forming a covalent "cleavage complex" where the DNA ends are tethered to the protein [5, 17]. This complex is the primary target for fluoroquinolone antibiotics, which act as topoisomerase poisons by intercalating into the DNA at the cleavage site and stabilizing the complex [1, 7, 12]. This stabilization prevents DNA religation, leading to the accumulation of permanent double-strand breaks and the stalling of replication forks, which triggers the SOS response and results in rapid bacterial cell death [6, 11, 18]. While highly effective for treating diverse infections, the clinical utility of drugs targeting this complex is challenged by the emergence of resistance mutations in the quinolone resistance-determining regions (QRDR) and significant safety concerns, including musculoskeletal and neurological toxicities [13, 15].

Other names

Quinolone-DNA-enzyme complexCleavable complexTernary topoisomerase complexDNA gyrase-DNA complexTopoisomerase IV-DNA complexGyrase-DNA-quinolone complex

Stabilization of the enzyme-DNA cleavage complex (topoisomerase poisoning), inhibition of DNA religation, and induction of lethal double-strand DNA breaks [1, 5, 13].