Verbascoside Protects Mice From Clostridial Gas Gangrene by Inhibiting the Activity of Alpha Toxin and Perfringolysin O.

Gas gangrene, caused mainly by the anaerobic bacterium Clostridium perfringens (C. perfringens), causes death within 48 h of onset. Limited therapeutic strategies are available, and it is associated with extremely high mortality. Both C. perfringens alpha toxin (CPA) and perfringolysin O (PFO) are important virulence factors in the development of gas gangrene, suggesting that they are therapeutic targets. Here, we found that verbascoside, a phenylpropanoid glycoside widely distributed in Chinese herbal medicines, could effectively inhibit the biological activity of both CPA and PFO in hemolytic assays. The oligomerization of PFO was remarkably inhibited by verbascoside. Although no antibacterial activity was observed, verbascoside treatment protected Caco-2 cells from the damage caused by CPA and PFO. Additionally, infected mice treated with verbascoside showed significantly alleviated damage, reduced bacterial burden, and decreased mortality. In summary, verbascoside has an effective therapeutic effect against C. perfringens virulence both in vitro and in vivo by simultaneously targeting CPA and PFO. Our results provide a promising strategy and a potential lead compound for C. perfringens infections, especially gas gangrene.

Identification of the natural product paeonol derived from peony bark as an inhibitor of the Salmonella enterica serovar Typhimurium type III secretion system.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is an important zoonotic pathogen in public health and food safety. The type III secretion system (T3SS) encoded by Salmonella pathogenicity island (SPI) is a sophisticated molecular machine that facilitates active invasion, intracellular replication, and host inflammation. Due to increasing antibiotic resistance, new therapeutic strategies that target the Salmonella T3SS have received considerable attention. In this study, paeonol was identified as an inhibitor of the S. Typhimurium T3SS. Paeonol significantly blocked the translocation of SipA into host cells and suppressed the expression of effector proteins without affecting bacterial growth in the effective concentration range. Additionally, S. Typhimurium-mediated cell injury and invasion levels were significantly reduced after treatment with paeonol, without cytotoxicity. Most importantly, the comprehensive protective effect of paeonol was confirmed in an S. Typhimurium mouse infection model. Preliminary mechanistic studies suggest that paeonol inhibits the expression of effector proteins by reducing the transcription level of the SPI-1 regulatory pathway gene hilA. This work provides proof that paeonol could be used as a potential drug to treat infections caused by Salmonella.