Polydatin as a natural ClpP modulator for combating methicillin-resistant Staphylococcus aureus infection

Methicillin resistant Staphylococcus aureus, MRSA, is a major cause of hospital acquired infections and poses a serious therapeutic challenge because of multidrug resistance and potent virulence. Targeting virulence rather than bacterial growth may provide an alternative strategy to combat MRSA infection. This study investigated polydatin, a stilbenoid glucoside from Polygonum cuspidatum, as a potential antivirulence agent targeting caseinolytic protease P, ClpP.

ClpP inhibitory activity was evaluated by enzymatic assay. The effects of polydatin on bacterial growth, hemolytic activity, virulence gene expression, adhesion to fibrinogen, and host cell invasion were assessed in vitro. Target engagement was examined by thermal shift assay, fluorescence quenching, and computational simulation. Therapeutic efficacy was evaluated in a murine pneumonia model.

Polydatin showed limited antibacterial activity but significantly inhibited ClpP and reduced the expression of key virulence factors, including Hla, PVL, and RNAIII. It also impaired bacterial adhesion to fibrinogen and invasion of host cells. Binding studies supported the interaction between polydatin and ClpP. In vivo, polydatin markedly alleviated S. aureus induced pneumonia, as shown by reduced lung bacterial burden, lower inflammatory cytokine levels, and attenuated tissue injury.

Polydatin attenuates MRSA pathogenicity by targeting ClpP associated virulence regulation rather than bacterial viability. These findings identify polydatin as a promising antivirulence candidate and provide a basis for developing alternative therapeutic strategies against MRSA infections.