Structural and Dynamic Implications of the R136H Mutation in DNA GyrB: Insights into Antimicrobial Resistance and Novobiocin Efficacy

Abstract

Antimicrobial resistance, amplified by the overuse and misuse of antibiotics, poses a significant global health threat. This study investigates the molecular basis of resistance associated with the R136H point mutation in DNA gyrase, an enzyme targeted by antibiotics such as novobiocin. Through molecular dynamics simulations, we assessed the impact of the R136H mutation on the binding, dynamics and stability of the protein-novobiocin complex. Our findings indicate that the R136H mutation significantly alters the inter residue interaction resulting in overall modification of protein’s secondary structure. These alterations likely contribute to the diminished antibacterial efficacy of novobiocin against the R136H mutant. The RIN analysis of novobiocin-bound wild-type and R136H mutant DNA-GyrB reveals key differences in inter-residue interactions, with the wild-type protein maintaining crucial ATP-binding interaction trails that are absent in the R136H variant. The MD simulation results reveal a notable difference in interaction patterns between two protein forms, with one variant exhibiting a diminished interaction profile. This study enhances understanding of the structural and dynamic implications of the R136H mutation, providing insights that could help to design of novel antimicrobial agents to combat resistance mechanisms.