Computational introspection of impact of mutation A90V and A90E in DNA gyrase a of Mycobacterium tuberculosis in developing resistance against Delafloxacin.

Quinolone group antibiotics have proven to be an effective drug against Mycobacterium tuberculosis. However, point mutation in DNA gyrase, one of the primary targets for quinolone antibiotics, has led to conformational alterations in the binding sites, leading to a change in drug pharmacodynamics. This has contributed to the development of drug-resistant strains such as multidrug-resistant strains (MDR) and an extreme drug-resistant strains (XDR). In this study, our objective was to find the impact of mutation A90V and A90E on DNA Gyrase A of Mycobacterium tuberculosis. Ten quinolone antibiotics were docked with DNA gyrase (3ILW_wild) to find the antibiotic with the highest binding affinity and favorable interactions. Delafloxacin forms a stable energy complex with - 8.6 kcal/mol, among all docked quinolone antibiotics. Two-point mutation A90E and A90V at position 90 were introduced in the 3ILW_wild model, and generated mutant models 3ILW_A90E and 3ILW_A90V and were docked again with the Delafloxacin to observe the changes in interaction due to mutation. A comparative molecular dynamics simulation study for the complex of Delafloxacin with 3ILW_wild, 3ILW_A90E, and 3ILW_A90V were conducted for 100ns to observe the conformational changes, fluctuations, compactness, and binding pattern. Structural dynamics due to the mutations A90V and A90E, and its effect on the shape and geometry of the Delafloxacin binding site of DNA gyrase before and after the mutation, can help in understanding the mechanism behind resistance and also in developing novel, swift-acting antibiotics with better efficacy.