- Topoisomerases are critical targets for antibiotics, and their role in antibiotic resistance represents a significant clinical challenge. DNA gyrase and Topoisomerase IV, both Type IIA topoisomerases in bacteria, are the primary targets of quinolone and fluoroquinolone antibiotics, which are essential broad-spectrum antimicrobial agents.
- Bacterial resistance to these antibiotics frequently develops through mutations in the genes encoding DNA gyrase (gyrA and gyrB) and Topoisomerase IV (parC and parE). These mutations typically occur in the quinolone resistance-determining regions (QRDRs), reducing the binding affinity of the antibiotics to their target enzymes while maintaining essential enzyme function.
- Plasmid-mediated quinolone resistance (PMQR) represents another mechanism of resistance involving topoisomerases. Genes such as qnr encode proteins that protect bacterial topoisomerases from quinolone inhibition. These genes can be horizontally transferred between bacterial species, contributing to the spread of resistance.
- The emergence of dual-targeting fluoroquinolones has complicated the resistance landscape. These drugs can simultaneously inhibit both DNA gyrase and Topoisomerase IV, requiring bacteria to develop mutations in both enzymes to achieve high-level resistance. However, bacteria have evolved stepwise mutation patterns that can eventually confer resistance to these dual-targeting agents.
- Novel topoisomerase-targeting compounds are being developed to combat resistance. These include novel bacterial type II topoisomerase inhibitors (NBTIs) and other compounds that interact with topoisomerases in ways distinct from traditional quinolones, potentially circumventing existing resistance mechanisms.
- Understanding the molecular mechanisms of topoisomerase-mediated antibiotic resistance has become crucial for drug development. Research continues to focus on developing new strategies to target these essential enzymes while avoiding or overcoming resistance mechanisms, including the development of hybrid molecules and novel binding site targeting.
