Abstract

The escalating crisis of antimicrobial resistance necessitates a paradigm shift toward host-directed therapies (HDTs) that circumvent pathogen evasion strategies. Here we show that the natural polyphenol resveratrol clears intracellular Salmonella Typhimurium ( S . Typhimurium) by orchestrating a multipronged strategy involving Salmonella -containing vacuole (SCV) disruption via ERK1/2 inhibition to liberate bacteria for enhanced autophagic clearance, concurrently reversing pathogen-induced G2/M cell cycle arrest. We identify High Mobility Group AT-Hook 2 (HMGA2) as a critical, previously unrecognized host dependency factor essential for Salmonella -driven cell cycle manipulation, which resveratrol targets to restrict bacterial replication. Furthermore, we characterize a resveratrol derivative, RV15, with enhanced potency and a distinct target profile validated by cellular thermal shift assay and proteome-wide reverse docking. This work underscores the potential of multipronged host modulation to eliminate intracellular pathogens that evade conventional antibiotics.