gyrA is a clinically validated therapeutic drug target that catalyzes changes in DNA topology by introducing negative supercoils into DNA. The broad-spectrum quinolones are hitherto the most potent antibacterial agents targeted toward gyrA. Increasing resistance to quinolones is accompanied by several mutations in the quinolone resistance-determining region of gyrA. In the present study, we report a comprehensive picture of the dynamic behavior of wild-type, T86I, and T86I/P104S mutants (MTs) of gyrA from Campylobacter jejuni in complex with ciprofloxacin to unravel the atomistic details of the mechanism underlying resistance to quinolones. Our simulation results reveal that no substantial conformational changes were observed. It was observed that these mutations disrupted residue interaction network landscape to a significant extent, which would affect ligand binding affinity. A distinctive pattern of dominant motions was clearly discernible in wild and MT gyrA forms. The results reported in this study associate gyrA mutations with quinolone resistance and would pave a way for facilitating wet laboratory researchers to develop gyrA MT-based therapeutic strategies against resistant pathogens.
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