Chalcone Attenuates Staphylococcus aureus Virulence by Targeting Sortase A and Alpha-Hemolysin

Area of Science:

• Microbiology
• Pharmacology
• Biochemistry

Background:

• Staphylococcus aureus infections pose a significant clinical challenge due to increasing antibiotic resistance.
• Developing novel anti-virulence strategies is crucial for combating resistant bacterial infections.
• Sortase A (SrtA) and alpha-hemolysin (Hla) are key virulence factors of S. aureus and promising therapeutic targets.

Purpose of the Study:

• To investigate the anti-virulence potential of chalcone against S. aureus.
• To determine chalcone's inhibitory effects on SrtA and Hla.
• To elucidate the mechanism of chalcone's action against S. aureus.

Main Methods:

• Fluorescence resonance energy transfer (FRET) assay to measure SrtA inhibition.
• Hemolysis assay to assess Hla activity inhibition.
• In vitro assays for biofilm formation, fibronectin binding, and bacterial invasion.
• Gene expression analysis (RT-qPCR) for hla and agrA.
• In vivo mouse infection model and molecular dynamics simulations.

Main Results:

• Chalcone significantly inhibited SrtA activity (IC50 = 53.15 μM) and Hla hemolysis (IC50 = 17.63 μM).
• Chalcone reduced protein A display, fibronectin binding, biofilm formation, and S. aureus invasion.
• Chalcone downregulated hla and agrA gene expression, protecting against Hla-mediated cell injury and reducing mortality in infected mice.
• Molecular dynamics simulations identified key interactions between chalcone and SrtA residues (Val168, Ile182, Arg197).

Conclusions:

• Chalcone exhibits significant anti-virulence properties against S. aureus by targeting both SrtA and Hla.
• Chalcone demonstrates therapeutic potential as a novel agent for treating S. aureus infections.
• The findings support chalcone as a promising candidate for developing new strategies against antibiotic-resistant S. aureus.