<b>The preservative isopropyl paraben targets the type III secretion system to inhibit </b><b><i>Salmonella enterica</i></b><b> serovar Typhimurium infection</b>

<i>Salmonella enterica</i>, a food- and water-borne pathogen, triggers food poisoning and enteric infections. The effectiveness of antibiotics against <i>Salmonella</i> infections is decreasing due to bacterial resistance. Developing novel antimicrobial agents is crucial and urgent. Here, we screened 550 natural compounds and identified 8 μg/mL isopropyl paraben (IPPB) effectively inhibited <i>Salmonella</i> <i>enterica</i> serovar Typhimurium (<i>S.</i> Typhimurium, ST) invasion of host cells without impacting bacterial growth, reducing the risk of developing bacterial resistance. Further investigation revealed that IPPB bound to the regulatory protein HilD and inhibited the transcription of the type III protein secretion system 1 (T3SS-1) regulatory genes <i>hilD</i>, <i>hilC</i> and <i>rtsA</i>. This interference blocked the production of T3SS-1 effectors. Importantly, IPPB exerted favorable therapeutic effects on both <i>G. mellonella</i> larvae and murine models infected with ST. These findings suggest that IPPB has potential as a novel antimicrobial agent, targeting the T3SS-1 of <i>Salmonella</i>.