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Targeting Biofilm Associated Staphylococcus aureus Using Resazurin Based Drug-susceptibility Assay
Published on: May 5, 2016
Drug-Repurposing Approach To Combat Staphylococcus aureus: Biomolecular and Binding Interaction Study
Vishakha Singh1, Poonam Dhankhar1, Vikram Dalal1
1Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee247667, India.
Abstract:
Staphylococcus aureus is considered as one of the most widespread bacterial pathogens and continues to be a prevalent cause of mortality and morbidity across the globe. FmtA is a key factor linked with methicillin resistance in S. aureus. Consequently, new antibacterial compounds are crucial to combat S. aureus resistance. Here, we present the virtual screening of a set of compounds against the available crystal structure of FmtA. The findings indicate that gemifloxacin, paromomycin, streptomycin, and tobramycin were the top-ranked potential drug molecules based on the binding affinity. Furthermore, these drug molecules were analyzed with molecular dynamics simulations, which showed that the identified molecules formed highly stable FmtA-inhibitor(s) complexes. Molecular mechanics Poisson-Boltzmann surface area and quantum mechanics/molecular mechanics calculations suggested that the active site residues (Ser127, Lys130, Tyr211, and Asp213) of FmtA are crucial for the interaction with the inhibitor(s) to form stable protein-inhibitor(s) complexes. Moreover, fluorescence- and isothermal calorimetry-based binding studies showed that all the molecules possess dissociation constant values in the micromolar scale, revealing a strong binding affinity with FmtAΔ80, leading to stable protein-drug(s) complexes. The findings of this study present potential beginning points for the rational development of advanced, safe, and efficacious antibacterial agents targeting FmtA.
Insights
New antibacterial compounds targeting FmtA, a key factor in Staphylococcus aureus resistance, were identified through virtual screening. Gemifloxacin, paromomycin, streptomycin, and tobramycin showed strong binding affinity, offering potential for developing new anti-S. aureus drugs.
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.
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