Infections refractory to standard antibiotic therapy are contributing to adverse treatment outcomes in patients suffering from deep-seated bacterial infections caused by increasingly resistant pathogens.Adjunctive str...Infections refractory to standard antibiotic therapy are contributing to adverse treatment outcomes in patients suffering from deep-seated bacterial infections caused by increasingly resistant pathogens.Adjunctive strategies targeting bacterial virulence factors have been con-sidered to aid the host immune response in fighting the infection.Previous studies suggest that the US FDA–approved anti-inflammatory drug diflunisal inhibits Staphylococcus aureus(SA)α-toxin expression by its interaction with the response regulator AgrA.We investigated the broader antivirulence properties of diflunisal against pathogenic strains of SA and established proof-of-concept for its efficacy in blocking SA virulence.Our studies reveal that diflunisal inhibitsα-toxin production,sensitizes SA to cationic antibiotics and human antimi-crobial peptides,inhibits the production of the golden pigment staphyloxanthin,and reduces biofilm formation.Molecular docking simula-tions revealed potential interactions between diflunisal and AgrA binding sites.In addition,sequence alignment of the SA AgrA response regulator demonstrated similarities to other response regulators involved in controlling virulence factor expression.Appreciation of the antivirulence properties of diflunisal supports a therapeutic strategy distinct from structurally similar compounds,such as salicylic acid.The repurposing of diflunisal may mitigate disease severity and provide a unique adjunctive tool in the treatment of SA infection.展开更多
基金supported by the US National Institutes of Health grants(R01-AI145325)This work was also supported in part by the UCSD Graduate Training Program in Cellular and Molecular Pharmacology through an institutional training grant from the National Institute of General Medical Sciences,T32 GM007752The funder had no role in the study design,data collection or analysis,decision to publish,or preparation of the manuscript.MSMS acknowledges his PDE scholarship by CNPq(200069/2024-1).
文摘Infections refractory to standard antibiotic therapy are contributing to adverse treatment outcomes in patients suffering from deep-seated bacterial infections caused by increasingly resistant pathogens.Adjunctive strategies targeting bacterial virulence factors have been con-sidered to aid the host immune response in fighting the infection.Previous studies suggest that the US FDA–approved anti-inflammatory drug diflunisal inhibits Staphylococcus aureus(SA)α-toxin expression by its interaction with the response regulator AgrA.We investigated the broader antivirulence properties of diflunisal against pathogenic strains of SA and established proof-of-concept for its efficacy in blocking SA virulence.Our studies reveal that diflunisal inhibitsα-toxin production,sensitizes SA to cationic antibiotics and human antimi-crobial peptides,inhibits the production of the golden pigment staphyloxanthin,and reduces biofilm formation.Molecular docking simula-tions revealed potential interactions between diflunisal and AgrA binding sites.In addition,sequence alignment of the SA AgrA response regulator demonstrated similarities to other response regulators involved in controlling virulence factor expression.Appreciation of the antivirulence properties of diflunisal supports a therapeutic strategy distinct from structurally similar compounds,such as salicylic acid.The repurposing of diflunisal may mitigate disease severity and provide a unique adjunctive tool in the treatment of SA infection.
