Structure-Based\nDiscovery of Symmetric Disulfides\nfrom Garlic Extract as Pseudomonas aeruginosa Quorum Sensing Inhibitors

Microorganisms are the most common cause of food spoilage. Pseudomonas aeruginosa is a common foodborne pathogen\nthat causes food spoilage and poses a serious threat to food safety.\nAs a crucial target in antitoxicity strategies, the quorum sensing\n(QS) system shows promising potential for further development. The\ngarlic extract diallyl disulfide exhibits inhibitory activity against\nthe QS system of P. aeruginosa, with\ndisulfide bonds serving as the active component. However, the biological\nactivity of other symmetric disulfides has not been investigated in\nthis capacity. The study synthesized 39 disulfide bond-containing\nanalogs and evaluated their activity as quorum sensing inhibitors\n(QSIs). The results showed that <i>p</i>-hydroxyphenyl substitution\ncan replace the allyl groups while maintaining strong biological activity.\nThe virulence factors production was reduced by compound <b>2i</b>, with the strongest inhibitory effect being observed on elastase\nproduction. Synergistic inhibition was observed in the presence of\nantibiotics like ciprofloxacin and tobramycin. <b>2i</b> successfully\ninhibited P. aeruginosa infection in\nthe Galleria mellonella larvae model.\nPrimary mechanism studies using transcriptome, surface plasmon resonance\nand molecular docking suggested that <b>2i</b> inhibits the\nQS system by targeting the LasR protein. Thus, compound <b>2i</b> could be used in developing QSIs for the control of P. aeruginosa infections.