Molecular dynamics simulations to investigate Mycobacterium tuberculosis DNA-gyrase-fluoroquinolone complexes

The widespread use of fluoroquinolone antibiotics to treat Mycobacterium tuberculosis (Mtb) infections has led to a rise in fluoroquinolone-resistant Mtb strains, mainly due to specific mutations in the target DNAgyrase. To overcome resistance and to develop treatment alternatives, a deeper understanding of fluoroquinolone’s mechanism of action is necessary. In this study we performed molecular dynamics (MD) simulations on experimentally derived complexes of wild-type and Ala90Ser mutated Mtb DNA gyrase with three fluoroquinolones – moxifloxacin, gatifloxacin, and levofloxacin. The differences in binding between the three drugs and the impact of the Ala90Ser mutation were analyzed at molecular level. Key interactions between gyrase amino acids, DNA nucleotides, and Mg 2+ cofactor with the fluoroquinolone ligands, were identified. The ranking of fluoroquinolones according to the stability of their DNA-gyrase complexes, binding energies, and key binding site residues, was in accordance with the in vitro reversibility assay data and the clinical effects of the drugs, thus validating the obtained MD results. Overall, our study contributes to better understanding of the molecular mechanisms underlying fluoroquinolone activity, and demonstrates the potential of the MD simulations to predict the drugs’ behavior within Mtb DNA-gyrase complexes. • Molecular dynamics (MD) simulations on crystallographic complexes of both wild-type and Ala90Ser mutated Mycobacterium tuberculosis DNA-gyrase with three fluoroquinolones (moxifloxacin, gatifloxacin, and levofloxacin), were performed; • The differences in binding between the three drugs and the role of the Ala90Ser mutation were analyzed based on complexes stability, ligand interaction energies, and H-bond analysis; • Key interactions between amino acids, DNA nucleotides, and Mg 2+ cofactor with the bound fluoroquinolone ligands were identified; • The ranking of fluoroquinolones according to the complexes stability, binding energies, and key binding site residues was in accordance with the in vitro and clinical data.