Transcriptomic Analysis Reveals the Inhibitory Mechanism of Fisetin Against the Pathogenicity of Aeromonas hydrophila

<i>Aeromonas hydrophila</i> is an important zoonotic bacterium that is related to multiple diseases in humans, terrestrial animals, and aquatic animals. Bacterial septicemia caused by <i>A. hydrophila</i> often results in high mortality and severe economic losses. Antibiotics, the major approach to dealing with bacterial infections, are limited due to the occurrence of antibiotic resistance. Anti-virulence strategies provide a promising approach to combat resistant bacterial infections. Here, growth curves, hemolysis, biofilm formation, and animal studies were performed to investigate the effect of fisetin against <i>A. hydrophila.</i> Moreover, RNA-seq technology was employed to determine the potent mechanism of fisetin. The results showed that fisetin could dose-dependently reduce the hemolytic activities mediated by aerolysin and hinder biofilm formation. Animal studies showed that treatment with 50 mg/kg fisetin could remarkably reduce the mortality to 40% in the infected group compared with fish in the fisetin-free group. Further, transcriptome analysis demonstrated that there were 565 differentially expressed genes (DEGs) after treatment with 16 μg/mL fisetin. Fisetin significantly impacted the pathways related to oxidative phosphorylation, the citrate cycle, and virulence factor regulation. Furthermore, 159 virulence-related genes were influenced after fisetin treatment. Collectively, these findings revealed that fisetin could mitigate the pathogenicity of <i>A. hydrophila</i> by affecting oxidative phosphorylation and the citrate cycle pathway as well as inhibiting the production of virulence factors. The study not only identified a powerful substance for managing <i>A. hydrophila</i>-associated diseases in aquaculture but also clarified the mechanism of plant medicines in controlling diseases caused by bacterial pathogens.