Exploring the potential of isorhapontigenin: attenuating virulence through MgrA-mediated regulation.

Unlabelled: The emerging prevalence of drug-resistant isolates underscores the urgent need for alternative therapeutic strategies due to the declining effectiveness of traditional antibiotics in clinical settings. MgrA, a key virulence regulator in , orchestrates the expression of numerous virulence factors. Here, we report the discovery of isorhapontigenin, a methoxylated analog of resveratrol, as a potential anti-virulence agent against . Isorhapontigenin effectively inhibits the hemolytic activity of in a non-bactericidal manner. Additionally, it significantly reduces the cytotoxicity of and impairs its ability to survive in macrophages. Mechanistically, isorhapontigenin modulates the expression of virulence factors, dose-dependently downregulating and upregulating the MgrA-regulated gene . Electrophoretic mobility shift assays demonstrated that isorhapontigenin inhibits the binding of MgrA to the promoter in a dose-dependent manner. Thermal shift assays confirmed the direct interaction between isorhapontigenin and the MgrA protein. The experiments demonstrated that isorhapontigenin significantly reduced the area of skin abscesses and improved survival in a pneumonia model while decreasing bacterial burden and inflammation in the lungs. In conclusion, isorhapontigenin holds potential as a candidate drug for further development as an anti-virulence agent for treating infections.

Importance: The emergence of antibiotic-resistant strains presents a formidable challenge to public health, necessitating novel approaches in combating these pathogens. Traditional antibiotics are becoming increasingly ineffective, leading to a pressing need for innovative therapeutic strategies. In this study, targeting virulence factors that play a crucial role in the pathogenesis of bacterial infections offers a promising alternative to circumvent resistance mechanisms. The discovery of isorhapontigenin as an inhibitor of virulence represents a significant advance in anti-virulence therapy.