Computational Insights into Moxifloxacin Resistance Conferred in Asn499 Mutants of <i>Mycobacterium tuberculosis</i> DNA Gyrase

The mycobacterial enzyme gyrase is the target of second-line tuberculosis (TB) drugs, fluoroquinolones. Emerging mutations in DNA gyrase subunit B including Asparagine (Asn)499Aspartic acid (Asp) and Asn499Lysine (Lys) cause resistance to fluoroquinolones like moxifloxacin (MFX). In this study, we attempted to discover the moxifloxacin resistance using in silico techniques such as molecular docking and molecular dynamics simulation. 10 ns of molecular dynamic simulation of gyrase-DNA-Moxifloxacin complex was performed with GROMACS and root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg) were calculated to examine the influence of mutation on the stability of the complex. Structural analysis showed that the stability of cleaved complex of wild type was well kept during simulation, while mutant complexes showed unstable states through the calculation of RMSD and Rg. Also, the distance between Tyrosine (Tyr)129, amino acid crucial for function of gyrase, and DNA phosphate in mutant complexes were extended compared with wild type. Binding free energy of moxifloxacin calculated using molecular docking and Molecular Mechanics/Poisson-Boltzmann surface area (MM-PBSA) methods showed the remarkable decreases in the mutant systems comparing with wild one. This study will make contribution to designing of new fluoroquinolones for controlling of drug-resistant tuberculosis.