Fisetin inhibits Salmonella Typhimurium type III secretion system regulator HilD and reduces pathology in vivo

Salmonella enterica is an important zoonotic intracellular bacterial pathogen that is capable of causing infections ranging from localized gastroenteritis to fatal systemic infection in humans and food-producing animals. The increasing antibiotic resistance in Salmonella isolates, especially the emergence of MDR and newer XDR strains, has compromised the efficacy of conventional antimicrobial therapy for Salmonella 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 Salmonella 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 Salmonella invasion. Fisetin appears to interfere with the interaction between HilD and its relevant promoters, thereby decreasing the transcription of hilA, 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 Salmonella 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-Salmonella drugs targeting T3SS-1.