In silico evaluation of new fluoroquinolones as possible inhibitors of bacterial gyrases in resistant Gram-negative pathogens

Antibiotic resistance has become a serious global health problem in the 21st century requiring urgent remedial action, as high levels of resistance in several micro-organisms spread rapidly. This research seeks to identify a new molecule with inhibitory activity against DNA gyrase in Gram-negative microorganisms resistant to fluoroquinolones, through in silico models starting from a group of compounds designed in a previous study. AutoDock was used for the molecular docking of the 9 new molecules analogous to ciprofloxacin optimized through the semi-empirical method PM6, with gyrA Wild Type and Mutant Type of C. jejuni, E. coli, N. gonorrhoeae, P. aeruginosa, S. enteritidis and S. typhi; where the molecule with the highest affinity for the DNA gyrase was selected as the one with the best binding free energy parameters and inhibition constant, to estimate the spontaneity and the IC₅₀ of the process respectively. Subsequently, a retrospective docking was performed for the validation of the results obtained with the new molecules. Molecular docking results position Molecule 7 as the one with the highest affinity for gyrA in 5 microorganisms, with binding free energy values lower than -7.0 kcal/mol and small inhibition constant compared to those obtained in ciprofloxacin. Moreover, the validation of these results in the gyrA MT systems of S. typhi, E. coli and P. aeruginosa, suggest a good degree of reliability in the affinity shown by the new fluoroquinolones with their protein target. Finally, Molecule 7 is nominated as a potential drug with good antibacterial activity so that it can be evaluated in vitro.