Drug-Repurposing Approach To Combat Staphylococcus aureus: Biomolecular and Binding Interaction Study

Area of Science:

• Microbiology
• Drug Discovery
• Computational Chemistry

Background:

• Staphylococcus aureus is a major global pathogen causing significant mortality and morbidity.
• Antibiotic resistance in S. aureus, particularly methicillin resistance, necessitates the development of novel antibacterial agents.
• FmtA is identified as a critical factor associated with methicillin resistance in S. aureus.

Purpose of the Study:

• To perform virtual screening of compounds against the FmtA protein structure.
• To identify potential drug molecules that can inhibit FmtA activity.
• To provide a basis for developing new antibacterial agents against S. aureus.

Main Methods:

• Virtual screening of a compound library against the FmtA crystal structure.
• Molecular dynamics simulations to analyze protein-inhibitor complex stability.
• Molecular mechanics Poisson-Boltzmann surface area and QM/MM calculations to identify key active site residues.
• Fluorescence and isothermal calorimetry-based binding studies to determine binding affinity.

Main Results:

• Gemifloxacin, paromomycin, streptomycin, and tobramycin were identified as top-ranked potential inhibitors of FmtA.
• Molecular dynamics simulations confirmed the formation of highly stable complexes between FmtA and the identified inhibitors.
• Key active site residues (Ser127, Lys130, Tyr211, Asp213) were found to be crucial for stable protein-inhibitor interactions.
• Experimental binding studies confirmed strong binding affinities (micromolar dissociation constants) with FmtA.

Conclusions:

• The identified compounds (gemifloxacin, paromomycin, streptomycin, tobramycin) show significant potential as antibacterial agents targeting FmtA.
• Stable FmtA-inhibitor complexes formed by these molecules suggest a viable therapeutic strategy.
• This study provides a foundation for the rational design of novel, effective, and safe antibacterial drugs against S. aureus.