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The increasing antibiotic resistance in\n            <jats:italic>Salmonella<\/jats:italic>\n            isolates, especially the emergence of MDR and newer XDR strains, has compromised the efficacy of conventional antimicrobial therapy for\n            <jats:italic>Salmonella<\/jats:italic>\n            infections. Hence, it is desirable to develop alternative therapeutic means to tackle the antimicrobial resistance crisis. In this study, we screened plant-derived compounds to identify inhibitors of\n            <jats:italic>Salmonella<\/jats:italic>\n            invasion of host cells. These efforts identified fisetin as a possible protector against infection. Further mechanistic studies revealed that fisetin suppressed the function of type III secretion system 1 (T3SS-1), the virulence determinant critical for\n            <jats:italic>Salmonella<\/jats:italic>\n            invasion. Fisetin appears to interfere with the interaction between HilD and its relevant promoters, thereby decreasing the transcription of\n            <jats:italic>hilA<\/jats:italic>\n            , the central transcriptional regulator that functions to activate the expression of T3SS-1 effector proteins and structural elements. In addition, administration of fisetin in the\n            <jats:italic>Salmonella<\/jats:italic>\n            murine infection model resulted in reduced bacterial colonization, alleviation of histopathological destruction, and decreased proinflammatory cytokine levels. Taken together, our study establishes that the natural compound fisetin can be used as a lead compound for the development of anti-\n            <jats:italic>Salmonella<\/jats:italic>\n            drugs targeting T3SS-1.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>Salmonella spp. remains a major worldwide health concern that causes significant morbidity and mortality in both humans and animals. The spread of antimicrobial resistant strains has declined the efficacy of conventional chemotherapy. Thus, novel anti-infection drugs or strategies are needed. Anti-virulence strategy represents one of the promising means for the treatment of bacterial infections. In this study, we found that the natural compound fisetin could inhibit Salmonella invasion of host cells by targeting SPI-1 regulation. Fisetin treatment impaired the interaction of the regulatory protein HilD with the promoters of its target genes, thereby suppressing the expression of T3SS-1 effectors as well as structural proteins. Moreover, fisetin treatment could reduce pathology in the Salmonella murine infection model. Collectively, our results suggest that fisetin may serve as a promising lead compound for the development of anti-Salmonella drugs.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.02406-23","type":"journal-article","created":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T14:00:34Z","timestamp":1702303234000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["Fisetin inhibits\n            <i>Salmonella<\/i>\n            Typhimurium type III secretion system regulator HilD and reduces pathology\n            <i>in vivo<\/i>"],"prefix":"10.1128","volume":"12","author":[{"given":"Siqi","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University  , Changchun, Jilin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2639-2114","authenticated-orcid":false,"given":"Hongtao","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University  , Changchun, Jilin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyan","family":"Shu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Center for Pathogen Biology and 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