Icariside II suppresses Staphylococcus aureus biofilms and prevents virulence rebound through SarX and SarZ network modulation

While the natural flavonol glycoside Icariside II (Baohuoside I) is known to suppress staphylococcal virulence by targeting the SarZ regulator the exact mechanisms driving its profound biofilm-eradicating capacity remained a critical paradox. Here we identify the master regulator SarX as the primary and direct functional target responsible for the anti-biofilm efficacy of Icariside II.

Through integrating multi-omics profiling targeted genetic ablations (ΔsarX and ΔsarZ) and biochemical interaction assays we demonstrate that Icariside II physically binds to SarX and neutralizes its transcriptional activation of the icaADBC operon effectively dismantling the protective extracellular matrix. Most importantly, the genetic loss of sarX triggers a systemic network rewiring that massively upregulates key hemolysins such as gamma-hemolysin (HlgCB), Staphopain B, and LukDv alongside the KdpCDE stress adaptation transport system.