Abstract

Tuberculosis (TB) is still a major public health problem, especially because of the ever-growing dominance of microbial resistance especially multidrug and extensively drug-resistant forms of Mycobacterium tuberculosis. One target for fluoroquinolone antibiotics is DNA gyrase A, an important enzyme in the process of DNA replication. Computational study (structure validation, physiochemical study and molecular docking) of the clinically relevant mutations (G88A, G88C, A90E, A90V, D94G, D94H) of gyrA gene. High overall structural conservation and a small comparative range of conformational deviation with good stereochemical quality across the models of the mutants ensured that they were reliable. The stability and hydropathic properties of mutants, determined using the physiochemical Profiling, were different with a notably decreased stability for G88C. Third- and fourth-generation fluoroquinolones were docked to the wild-type DNA gyrase and the binding energy of Delafloxacin (−8.6 kcal/mol) was the lowest, making it the most potent inhibitor. A comparative interaction analysis revealed that the change G88A retains interactions with a cognate ligand, whereas the change G88C has a significant decrease in binding affinity and hydrogen-bond interactions in vitro, which suggests a resistance-associated phenotype. These results highlight the significance of the QRDR mutation for the binding and unbinding dynamics of quinolones, and may be relevant to novel ideas for next-generation anti-tubercular therapeutic and targeted drug design for resistance.

Key words: Molecular Docking, Mutation, Multidrug resistant (MDR), Extensively drug resistant(XDR), QRDR