A small molecule utilizes both antivirulence and host-directed mechanisms to combat bacterial infection

Antimicrobial resistance is progressively undermining the efficacy of conventional antibiotics, and intracellular infections caused by Salmonella typhimurium (ST) remain difficult to eradicate, underscoring the need for alternative therapeutic strategies.

To identify natural small molecules possessing both antivirulence and host-directed activities against ST infection, and further characterize their mechanisms of action.

A dual-screening strategy was employed to identify compounds that inhibit both ST invasion and intracellular replication. RNA sequencing, quantitative polymerase chain reaction, western blot analysis, β-galactosidase reporter assay, scanning electron microscopy, and flow cytometry were performed to investigate the mode of action of the active compound. A murine enterocolitis model was established to evaluate its therapeutic efficacy.

Ferulic acid (FA) emerged as a dual-acting inhibitor. FA suppressed SPI-4 promoter PsiiA activity, reduced SPI-4 transcription and SiiE secretion, and impaired SiiE-dependent adhesion, thereby limiting bacterial invasion. In parallel, FA suppressed macrophage STAT3 phosphorylation and enhanced NRF2 signaling, leading to reduced intracellular ferrous iron and ferroptosis, which in turn restricted intracellular bacterial replication. Furthermore, FA treatment alleviated ST-induced enterocolitis in mice.

FA protects against ST infection by attenuating bacterial virulence and modulating host iron homeostasis. These findings support its potential as a combined antivirulence and host-directed therapeutic candidate.