title: Dynamics of fluoroquinolones induced resistance in DNA gyrase of Mycobacterium tuberculosis.
abstract: DNA gyrase is a validated target of fluoroquinolones which are key components of multidrug resistance tuberculosis (TB) treatment. Most frequent occurring mutations associated with high level of resistance to fluoroquinolone in clinical isolates of TB patients are A90V, D94G, and A90V-D94G (double mutant [DM]), present in the larger subunit of DNA Gyrase. In order to explicate the molecular mechanism of drug resistance corresponding to these mutations, molecular dynamics (MD) and mechanics approach was applied. Structure-based molecular docking of complex comprised of DNA bound with Gyrase A (large subunit) and Gyrase C (small subunit) with moxifloxacin (MFX) revealed high binding affinity to wild type with considerably high Glide XP docking score of -7.88 kcal/mol. MFX affinity decreases toward single mutants and was minimum toward the DM with a docking score of -3.82 kcal/mol. Docking studies were also performed against 8-Methyl-moxifloxacin which exhibited higher binding affinity against wild and mutants DNA gyrase when compared to MFX. Molecular Mechanics/Generalized Born Surface Area method predicted the binding free energy of the wild, A90V, D94G, and DM complexes to be -55.81, -25.87, -20.45, and -12.29 kcal/mol, respectively. These complexes were further subjected to 30 ns long MD simulations to examine significant interactions and conformational flexibilities in terms of root mean square deviation, root mean square fluctuation, and strength of hydrogen bond formed. This comparative drug interaction analysis provides systematic insights into the mechanism behind drug resistance and also paves way toward identifying potent lead compounds that could combat drug resistance of DNA gyrase due to mutations.
authors.affiliation: a Department of Biotechnology , Panjab University , Chandigarh 160014.
authors.forename: Bharati
authors.initials: B
authors.lastname: Pandey
authors.affiliation: b Kusuma School of Biological Sciences, Indian Institute of Technology Delhi , New Delhi , India.
authors.forename: Sonam
authors.initials: S
authors.lastname: Grover
authors.affiliation: c School of Biotechnology , Jawaharlal Nehru University , New Delhi 110067 , India.
authors.forename: Chetna
authors.initials: C
authors.lastname: Tyagi
authors.affiliation: d Department of Bioscience and Biotechnology , Banasthali University , Tonk 304022 , Rajasthan , India.
authors.forename: Sukriti
authors.initials: S
authors.lastname: Goyal
authors.affiliation: d Department of Bioscience and Biotechnology , Banasthali University , Tonk 304022 , Rajasthan , India.
authors.forename: Salma
authors.initials: S
authors.lastname: Jamal
authors.affiliation: e Department of Biotechnology , TERI University , Vasant Kunj , New Delhi 110070.
authors.forename: Aditi
authors.initials: A
authors.lastname: Singh
authors.affiliation: a Department of Biotechnology , Panjab University , Chandigarh 160014.
authors.forename: Jagdeep
authors.initials: J
authors.lastname: Kaur
authors.affiliation: c School of Biotechnology , Jawaharlal Nehru University , New Delhi 110067 , India.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
mesh_terms: D027081:DNA Gyrase / Q000737:chemistry / Q000235:genetics*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D024841:Fluoroquinolones / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D000077266:Moxifloxacin / Q000737:chemistry* / Q000494:pharmacology; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry; D014376:Tuberculosis / Q000188:drug therapy* / Q000235:genetics / Q000382:microbiology
chemical_list: D024841:Fluoroquinolones; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase; D000077266:Moxifloxacin
keywords: DNA gyrase; Mycobacterium tuberculosis; drug resistance; fluoroquinolones; molecular dynamics