Gyrase and Topoisomerase IV as Antibacterial Targets for Gepotidacin and Zoliflodacin: Teaching Old Enzymes New Tricks

The essential bacterial type II topoisomerases gyrase and topoisomerase IV have been exploited as the therapeutic targets of fluoroquinolone antibacterials for over four decades. Despite their broad utility, the effectiveness of fluoroquinolones has been increasingly undermined by the widespread emergence of target-mediated resistance, highlighting the need for alternative therapeutic strategies. Recent advances have produced two mechanistically distinct classes of gyrase/topoisomerase IV-targeted antibacterials: the triazaacenaphthylenes and the spiropyrimidinetriones. The first-in-class agents gepotidacin and zoliflodacin, respectively, were approved for human use in 2025, representing the first new antibacterial classes targeting these enzymes in decades. This commentary examines the mechanisms of action of these agents, contrasts their interactions with gyrase and topoisomerase IV relative to fluoroquinolones, and considers their potential to address resistance while preserving the long-term clinical viability of therapy directed against the bacterial type II topoisomerases.