Structure-based identification of salvianolic acid B as an inhibitor targeting Salmonella InvC ATPase.

Abstract

Multidrug-resistant (MDR) Salmonella poses a significant global health threat. The Type III Secretion System 1 (T3SS-1) and its ATPase InvC are crucial for virulence and promising drug targets. Through structure-based virtual screening, we identified Salvianolic acid B (SA-B) as an inhibitor of InvC. To rigorously characterize its interaction, we performed extensive molecular dynamics simulations, which revealed a 'dynamic yet stable' binding mode within the ATP-binding pocket. Subsequent experimental validation confirmed that SA-B directly binds the InvC ATP pocket and inhibits its ATPase activity. Consequently, SA-B inhibited T3SS-1-mediated effector secretion and reduced the invasion of host cells by S. Typhimurium in vitro, without affecting bacterial viability. Importantly, SA-B demonstrated significant therapeutic efficacy in Galleria mellonella and mouse infection models, improving survival and reducing bacterial burden. This study establishes SA-B as a promising anti-virulence lead compound targeting Salmonella InvC, offering a strategy that may mitigate antibiotic resistance by selectively disarming pathogen virulence mechanisms rather than targeting viability.