Isoliquiritigenin Attenuates Staphylococcus aureus Adhesion and Invasion Mechanisms to Counteract Staphylococcus aureus Pathogenicity and Infection

Lili Tian¹Jian Sun²Hong Jiang¹Hongjun Wang¹Jian Zheng¹Dacheng Wang³Libo Zhang^4*

• ¹Jinzhou Medical University, Jinzhou, China
• ²Beijing Vocational College of Agriculture, Beijing, China
• ³Jilin University, Changchun, China
• ⁴Northern Theater Command Postgraduate Training Base of Jinzhou Medical University General Hospital, Shenyang, China

Abstract Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant clinical challenge because of its virulence and resistance to conventional antibiotics. As resistance continues to rise, antivirulence strategies that target bacterial pathogenicity mechanisms without killing bacteria are gaining attention. In this study, we evaluated the ability of isoliquiritigenin (ISL), a natural compound, to inhibit S. aureus sortase A (SrtA), an enzyme responsible for anchoring surface proteins critical for bacterial adhesion and biofilm formation. Our results show that ISL effectively inhibits SrtA in a dose-dependent manner, with an IC₅₀ of 13.34 μg/mL, and disrupts bacterial adhesion to fibrinogen and fibronectin as well as biofilm formation without affecting bacterial growth. Fluorescence quenching assays confirmed a direct binding interaction between ISL and SrtA, which was further supported by molecular docking studies identifying key amino acid residues involved in this interaction. These findings suggest that ISL binds to SrtA in a reversible, noncovalent manner. In a murine pneumonia model, ISL treatment reduced the bacterial load in the lungs, improved survival, and alleviated tissue damage, highlighting its potential as an antivirulence agent. These findings support ISL as a promising candidate for MRSA infection treatment, offering a novel approach to combat antibiotic-resistant strains.