Molecular dynamics simulation guided analysis of the interaction between delafloxacin and Staphylococcus aureus gyrase mutants

Staphylococcus aureus is a highly virulent nosocomial pathogen producing a wide array of virulence factors to orchestrate a deadly disease. Delafloxacin is a fluoroquinolone antibiotic targeting gyrase to confer its antibacterial properties by stabilising DNA breakage. Due to the presence of certain mutations in gyrase A (GyrA), fluoroquinolone resistance has been reported. In this paper, the computational basis of delafloxacin resistance in S. aureus is studied. Computational techniques including molecular dynamics simulations simulation were applied to observe the effects of delafloxacin binding to gyrase coupled with MM-PBSA-based binding energy calculation and PCA to further ascertain the stability of the complexes. The mutation in gyrase did not cause any significant structural perturbation owing to delafloxacin binding. A significant change in free binding energy was seen in mutant–delafloxacin complexes in contrast to wild-type counterparts. The lowest (most negative) binding free energy obtained in the WT–delafloxacin complex indicated a better affinity and more stable interaction than the mutant complexes. The key residues of GyrA involved in interaction with delafloxacin were identified using their contribution to binding energy through the implementation of per-residue MM-PBSA decomposition. Delafloxacin failed to maintain stable interaction when bound to a mutant binding pocket and trans-located to an alternate site.