Mechanism of Antibiotic Resistancein Multidrug-Resistant Klebsiella spp.:Protein and Drug Interactions

Abstract

Background: Multi-drug-resistant Klebsiella pneumoniae poses a significant global health threat due to its resistance
mechanisms against multiple antibiotic classes. The SHV-1 β-lactamase enzyme, a type of serine-based β-lactamase,
plays a crucial role in hydrolyzing β-lactam antibiotics, contributing to treatment failures. Objective: This study
investigates the molecular interactions between tazobactam, a β-lactamase inhibitor, through computational approaches.
Materials and Methods: The PyMOL 2.5.2 tool was used for in silico analysis, and the three-dimensional structure of
SHV-1 β-lactamase was retrieved from the Protein Data Bank. Hydrogen atoms were incorporated after water molecules
by the AutoDockTools package. GROMACS 2025.1 with the AMBER99SB-ILDN force field was used for the MD
simulation, and ADME analysis was performed using the SwissADME web server. Results: Molecular docking using
AutoDock 4.2 revealed strong binding affinity (-9.46 kcal/mol) between tazobactam and SHV-1 β-lactamase, with key
interactions involving hydrogen bonds with ARG-205, MET-A186, THR-A71, and LYS-A234 residues. Molecular
dynamics simulations over 100 nanoseconds using GROMACS 2025.1 demonstrated complex stability with RMSD
fluctuations ranging from 0.15-0.2 nm after initial equilibration. RMSF analysis identified flexible regions (0.1-0.2 nm)
important for drug binding dynamics. The computational analysis was complemented by ADME profiling to assess
drug-like properties. Results indicate that tazobactam exhibits promising binding affinity and structural stability against
SHV-1 β-lactamase, supporting its therapeutic potential in combination therapy. Conclusion: This study provides
molecular-level insights into the mechanism of β-lactamase inhibition and contributes to understanding structure-
activity relationships essential for developing effective treatments against multidrug-resistant Klebsiella infections