Staphylococcus aureus DNA gyrase and topoisomerase IV (Gyrase/Topo IV)

Staphylococcus aureus DNA gyrase and topoisomerase IV are essential type II topoisomerases that regulate the topological state of DNA during replication, transcription, and recombination (UniProt, 2024). DNA gyrase, composed of GyrA and GyrB subunits, is unique in its ability to introduce negative supercoils into DNA, relieving torsional stress ahead of the replication fork (Hooper, 1997). Topoisomerase IV, consisting of GrlA (ParC) and GrlB (ParE) subunits, primarily functions to decatenate interlinked daughter chromosomes following DNA replication (Wang, 1996). These enzymes are the principal targets of fluoroquinolone antibiotics, which stabilize the enzyme-DNA cleavage complex, resulting in permanent double-strand breaks and bacterial cell death (Aldred et al., 2014). In S. aureus, topoisomerase IV is typically the primary target for most quinolones, while DNA gyrase acts as a secondary target (Antimicrobial Agents and Chemotherapy, 2000). The emergence of resistance through mutations in the quinolone resistance-determining regions (QRDR) of these enzymes is a major clinical concern, particularly in methicillin-resistant S. aureus (MRSA) strains (ACS, 2023). Novel inhibitors like zoliflodacin and gepotidacin are being developed to overcome this resistance by targeting different sites or mechanisms within these enzymes (International Journal of Molecular Sciences, 2023). Beyond quinolones, aminocoumarin antibiotics like novobiocin inhibit these enzymes by competing with ATP for binding to the B subunits (Journal of Antimicrobial Chemotherapy, 2024). Together, these enzymes represent a critical vulnerability in the bacterial life cycle and remain a focus for the development of next-generation antimicrobials.

Other names

DNA gyraseTopoisomerase IVGyrAGyrBGrlAGrlBParCParEType II topoisomeraseQuinolone targets

Fluoroquinolones act by stabilizing the covalent enzyme-DNA cleavage complex, which prevents DNA religation and leads to lethal double-strand breaks (Aldred et al., 2014). Aminocoumarins like novobiocin inhibit the enzymes by competitively binding to the ATP-binding site on the GyrB and ParE subunits, thereby blocking the energy source required for catalytic activity (UniProt, 2024).