Repurposing Diflunisal as an Antivirulence Agent Against Staphylococcus aureus

Area of Science:

• Microbiology and Infectious Diseases
• Pharmacology and Drug Repurposing
• Bacterial Pathogenesis

Background:

• Antibiotic resistance in Staphylococcus aureus (SA) poses a significant threat, leading to poor treatment outcomes in deep-seated infections.
• Targeting bacterial virulence factors offers a promising adjunctive strategy to bolster host immune response against resistant pathogens.
• Previous research indicates diflunisal may inhibit SA α-toxin expression via interaction with the AgrA response regulator.

Purpose of the Study:

• To investigate the broader anti-virulence properties of diflunisal against pathogenic Staphylococcus aureus strains.
• To establish proof-of-concept for diflunisal's efficacy in blocking SA virulence mechanisms.
• To explore diflunisal's potential as an adjunctive therapeutic agent for SA infections.

Main Methods:

• Experimental evaluation of diflunisal's effects on SA virulence factors, including α-toxin production, staphyloxanthin synthesis, and biofilm formation.
• Assessment of diflunisal's impact on SA susceptibility to cationic antibiotics and antimicrobial peptides.
• Molecular docking simulations to predict interactions between diflunisal and the AgrA binding site; sequence alignment of SA AgrA.

Main Results:

• Diflunisal significantly inhibited α-toxin production and staphyloxanthin pigment formation in SA.
• Diflunisal treatment sensitized SA to cationic antibiotics and human antimicrobial peptides.
• Reduced biofilm formation was observed in SA treated with diflunisal; molecular docking suggested AgrA interaction.

Conclusions:

• Diflunisal exhibits broad anti-virulence properties against Staphylococcus aureus, distinct from structurally similar compounds like salicylic acid.
• The repurposing of diflunisal presents a novel therapeutic strategy to mitigate SA disease severity.
• Diflunisal may serve as a valuable adjunctive treatment option for managing SA infections, particularly those refractory to standard antibiotics.