Bacterial DNA topoisomerase II and topoisomerase IV (DNA gyrase (often abbreviated as Gyrase) and topoisomerase IV (Topo IV))

Molecular Classification

Enzyme, Other: ATP-dependent DNA-modifying enzyme

Other Names

DNA gyrase, Topoisomerase IV, Type IIA topoisomerases, GyrA/GyrB, ParC/ParE

Disease Roles

Infection (primary role as drug target for bacterial infections and resistance)Other: Role in antimicrobial resistance development

Bacterial DNA topoisomerase II and topoisomerase IV Overview

DNA gyrase and DNA topoisomerase IV are essential bacterial type II topoisomerases that manage DNA topology during replication, transcription, and chromosomal segregation. DNA gyrase uniquely introduces negative supercoils and relaxes positive supercoils, while topoisomerase IV mainly decatenates intertwined daughter chromosomes and also relaxes supercoils. Both are heterotetrameric enzymes: gyrase is composed of GyrA and GyrB subunits, topoisomerase IV of ParC and ParE subunits. These enzymes are validated and clinically important antibacterial targets, especially for fluoroquinolones and newer drug classes. The widespread clinical use of these inhibitors has led to high rates of target-mediated resistance, making continued drug development against these targets a central focus in antibacterial chemotherapy.

Mechanism of Action

Stabilization of topoisomerase-DNA cleavage complexes leading to double-stranded DNA breaks (fluoroquinolones and related agents) Inhibition of ATPase activity (aminocoumarins) Allosteric inhibition (NBTIs)

Biological Functions

DNA supercoiling regulation (gyrase introduces negative supercoils)

Relaxation of positive supercoils (both gyrase and topoisomerase IV)

Decatenation (removal of knots/interlinked DNA, especially by topoisomerase IV)

Chromosome segregation during cell division

DNA replication and transcription support

Disease Associations

Infection (primary role as drug target for bacterial infections and resistance)

Other: Role in antimicrobial resistance development

Safety Considerations

Drug resistance: Widespread resistance, especially target-mediated, via point mutations
Adverse reactions: Drug class-specific, such as fluoroquinolone-related tendonopathy and CNS effects
Off-target effects: Potential toxicity with some inhibitor classes (aminocoumarins)
Cross-resistance: Shared mechanisms for multiple antibiotic classes targeting same enzymes

Interacting Drugs

Fluoroquinolones (e.g., ciprofloxacin, levofloxacin)

Aminocoumarins (target ATPase domains)

Novel bacterial topoisomerase inhibitors (NBTIs)

Zoliflodacin, gepotidacin

Simociclinones, cyclothialidines

Associated Biomarkers

Biomarker
Mutations in GyrA, GyrB, ParC, ParE genes (associated with drug resistance; used for monitoring susceptibility and resistance)
QRDR (quinolone resistance-determining region) mutations