Article summary
Abstract
DNA gyrase, a bacterial type IIA topoisomerase, remains a validated and privileged antibacterial target due to its essentiality in bacteria and absence in humans. Gyrase introduces negative supercoils into DNA via an ATP-dependent strand-passage cycle mediated by GyrA (DNA cleavage/re-ligation) and GyrB (ATPase), creating multiple pharmacological intervention points. Resistance to gyrase-targeting drugs arises from mutations in the quinolone resistance–determining region (QRDR), alterations in GyrB’s ATP pocket, plasmid-encoded protection (e.g., Qnr), drug-modifying enzymes, and efflux 4. This mini-review focuses on (i) gyrase biology and catalytic cycle; (ii) resistance mechanisms; and (iii) medicinal chemistry progress across four major inhibitor spaces: fluoroquinolones (poisons), GyrB ATP-competitive inhibitors (aminocoumarins and synthetics), novel bacterial topoisomerase inhibitors (NBTIs; e.g., zoliflodacin; gepotidacin), and natural/allosteric classes (simocyclinone, albicidin; recent allosteric series). We emphasize strategies that mitigate resistance, including dual targeting of gyrase and topoisomerase IV, distinct binding footprints orthogonal to QRDR, and optimization to evade efflux while improving safety.