Bacterial DNA gyrase and bacterial topoisomerase IV (Gyrase, Topo IV)

Molecular Classification

Enzyme, Topoisomerase, ATP-dependent topoisomerase, Type II topoisomerase

Other Names

Gyrase, Type II topoisomerase (bacterial), GyrA/B complex, Topo IV, ParC/ParE (in Gram-negative bacteria), GrlA/GrlB (in Gram-positive bacteria)

Disease Roles

Infection (these are essential for viability of most bacteria and are targets for antibacterial therapy)

Bacterial DNA gyrase and bacterial topoisomerase IV Overview

Bacterial DNA gyrase and topoisomerase IV are essential type II topoisomerases in bacteria. DNA gyrase introduces negative supercoils into bacterial DNA and relaxes positive supercoils, an activity essential for DNA replication and transcription. Topoisomerase IV primarily decatenates newly replicated DNA molecules, ensuring proper chromosome segregation during cell division, and also relaxes positive supercoils but does not introduce negative supercoiling[1][3][9]. Both enzymes are heterotetramers made up of A and B type subunits (GyrA/GyrB for gyrase; ParC/ParE or GrlA/GrlB for topo IV, depending on species), and both require ATP hydrolysis for their catalytic cycle[3][5]. They are the primary cellular targets of fluoroquinolone antibiotics, which either stabilize the enzyme-DNA cleavage complex (causing DNA breaks and bacterial cell death) or inhibit ATP binding and enzyme catalytic activity[2][4][6][7]. Resistance emerges primarily through point mutations in the drug-binding sites of their genes. Their centrality to bacterial DNA dynamics and the lack of close eukaryotic homologs make them important and validated targets for antibacterial drug discovery and development[2][4][6][8].

Mechanism of Action

Topoisomerase poisons: Drugs (e.g. fluoroquinolones) that stabilize the enzyme-DNA cleavage complex, leading to double-stranded DNA breaks and cell death.\nCatalytic inhibitors: Drugs (e.g. novobiocin) that inhibit ATPase activity required for enzyme function, blocking the supercoiling/decatenation cycle.

Biological Functions

Regulation of DNA supercoiling

Relaxation of DNA supercoils

Introduction/removal of DNA supercoiling (gyrase introduces negative supercoiling; both remove positive supercoiling)

Decatenation (unlinking) of newly replicated chromosomes (principally by topoisomerase IV)

Support of DNA replication, transcription, and chromosome segregation

Disease Associations

Infection (these are essential for viability of most bacteria and are targets for antibacterial therapy)

Safety Considerations

Resistance: Rapid evolution of resistance via point mutations in QRDRs of gyrA, gyrB, parC, and parE, as well as via efflux pumps
Selective toxicity: While drugs have high selectivity for bacterial topoisomerases, mammalian type II topoisomerases share some mechanistic similarities, necessitating careful dosage and monitoring.
Toxicity of fluoroquinolones: Class-specific issues include risk of tendinopathy, neuropathy, CNS effects; however, these are not related to manipulation of bacterial targets themselves.

Interacting Drugs

Ciprofloxacin

levofloxacin

norfloxacin

moxifloxacin

gemifloxacin

Nalidixic acid

oxolinic acid

Novobiocin (primarily gyrase)

coumermycin

GP6

Associated Biomarkers

Biomarker
Resistance-associated mutations in gyrA and gyrB (gyrase) and parC and parE (topoisomerase IV), especially within quinolone-resistance-determining regions (QRDR)
Not used for individual patient selection, but critical in microbiological surveillance of resistance.