Quinolones are widely used antibacterial drugs that target bacterial type II topoisomerases, gyrase and topoisomerase IV, which are essential for DNA replication and chromosome segregation. However, the overuse of quinolones has led to the emergence of resistant bacterial strains, threatening their clinical effectiveness. Quinolone resistance arises through three main mechanisms: target-mediated resistance, plasmid-mediated resistance, and chromosome-mediated resistance. Target-mediated resistance is the most common and is caused by mutations in gyrase and topoisomerase IV that weaken quinolone binding. Plasmid-mediated resistance involves genes on extrachromosomal elements that reduce quinolone binding or increase efflux. Chromosome-mediated resistance results from reduced porin expression or increased efflux pump activity, decreasing quinolone uptake. Quinolones inhibit topoisomerases by stabilizing DNA cleavage complexes, leading to DNA strand breaks and cell death. The mechanism of action involves interactions with the enzyme's active site, particularly through a water-metal ion bridge. Mutations in key residues, such as serine and acidic residues, disrupt this interaction, leading to resistance. Recent studies have shown that quinazolinediones, which lack the keto acid involved in the water-metal ion bridge, can still bind to topoisomerases and overcome resistance by interacting with different residues. Efforts to overcome quinolone resistance include developing new drugs that target the bacterial enzymes without relying on the water-metal ion bridge. Quinazolinediones, with specific substituents like the 3'-aminomethylpyrrolidinyl group, show promise in this regard. These compounds can bind to bacterial topoisomerases without affecting human enzymes, potentially reducing toxicity. Understanding these interactions is crucial for designing new quinolones that are effective against resistant strains and extending the clinical utility of these drugs.Quinolones are widely used antibacterial drugs that target bacterial type II topoisomerases, gyrase and topoisomerase IV, which are essential for DNA replication and chromosome segregation. However, the overuse of quinolones has led to the emergence of resistant bacterial strains, threatening their clinical effectiveness. Quinolone resistance arises through three main mechanisms: target-mediated resistance, plasmid-mediated resistance, and chromosome-mediated resistance. Target-mediated resistance is the most common and is caused by mutations in gyrase and topoisomerase IV that weaken quinolone binding. Plasmid-mediated resistance involves genes on extrachromosomal elements that reduce quinolone binding or increase efflux. Chromosome-mediated resistance results from reduced porin expression or increased efflux pump activity, decreasing quinolone uptake. Quinolones inhibit topoisomerases by stabilizing DNA cleavage complexes, leading to DNA strand breaks and cell death. The mechanism of action involves interactions with the enzyme's active site, particularly through a water-metal ion bridge. Mutations in key residues, such as serine and acidic residues, disrupt this interaction, leading to resistance. Recent studies have shown that quinazolinediones, which lack the keto acid involved in the water-metal ion bridge, can still bind to topoisomerases and overcome resistance by interacting with different residues. Efforts to overcome quinolone resistance include developing new drugs that target the bacterial enzymes without relying on the water-metal ion bridge. Quinazolinediones, with specific substituents like the 3'-aminomethylpyrrolidinyl group, show promise in this regard. These compounds can bind to bacterial topoisomerases without affecting human enzymes, potentially reducing toxicity. Understanding these interactions is crucial for designing new quinolones that are effective against resistant strains and extending the clinical utility of these drugs.