Piceatannol and its analogues alleviate Staphylococcus aureus pathogenesis by targeting β-lactamase biofilms and α-hemolysin.

β-Lactamases, biofilms and toxins pose challenges for combating S. aureus infection. Thus, identifying inhibitors that can restore bacterial sensitivity to antibiotics, destroy biofilms, and antitoxins is a promising way to develop alternative agents. In this study, we found that piceatannol (pit), along with its analogues resveratrol (ret) and pterostilbene (pts) bind with β-lactamase to inhibit its activity, and 96TYR, 58ILE and 66LYS were identified as the critical binding residues. Pit and pts reduced the ampicillin (Amp) and gentamicin (Gm) MICs against S. aureus and enhanced the bactericidal ability of Amp. Pit and its analogues inhibited the formation of S. aureus USA300. In addition, the pit analogues bound with α-hemolysin and suppressed the hemolysis activity of the bacterial culture supernatant. The mechanism analysis revealed that pit exhibited multiple potential binding modes with α-hemolysin. Pit significantly decreased the cytotoxicity and the adherence effect mediated by S. aureus and increased the survival rate of Galleria mellonella that infected with S. aureus, the pathological tissue damage of Galleria mellonella was alleviated by treatment with pit alone or in combination with Amp. Taken together, our findings identify promising compounds for the development of S. aureus infection inhibitors.