(Part 2) Molecular characterization of Mycobacterium ulcerans DNA gyrase and identification of mutations reduced susceptibility to quinolones in vitro

Abstract

  Buruli ulcer disease is a neglected necrotizing and disabling cutaneous tropical illness caused by Mycobacterium ulcerans (Mul). Fluoroquinolone (FQ), used in the treatment of this disease, has been known to act by inhibiting the enzymatic activities of DNA gyrase; however, the detailed molecular basis of these characteristics and the FQ resistance mechanisms in Mul remains unknown. In this study investigated the detailed molecular mechanism of Mul DNA gyrase and the contribution of FQ resistance in vitro using recombinant proteins from the Mul subsp. shinshuense and Agy99 strains with reduced sensitivity to FQs. Furthermore, the interaction between the amino acid residues of WT/mutant Mul DNA gyrase and side chains of FQ was assessed via molecular docking studies. This is the first elaborative study demonstrating the contribution of mutations in Mul DNA GyrA subunit to FQ resistance in vitro.