The root bark of Paeonia suffruticosa alleviates Staphylococcus aureus-induced pneumonia in mice by modulating toxin secretion and function.

Staphylococcus aureus, which is a major zoonotic pathogen, can cause various tissues infection and the prevalence of multidrug-resistant S. aureus causes more difficulty in treating the infectious diseases. Moutan Cortex (MC), tree peony root-bark, derived from the root bark of Paeonia suffruticosa Andrews, a key component in traditional Chinese herbal medicine for infections, inhibits α-hemolysin (Hlα) hemolytic activity of S. aureus. This study aimed to elucidate the characteristics of Hlα inhibition and the anti-inflammatory mechanisms of the herb Moutan Cortex decoction (MCD, the aqueous extract of MC). LC-MS identified active components including paeonol, paeoniflorin, glabrone, and ellagic acid. Network pharmacology predicted anti-inflammatory effects via modulation of MAPK-NF-κB and IL-1β signaling pathways. Animal studies demonstrated that MCD significantly reduced Hlα accumulation in lung tissue, suppressed NF-κB signaling-mediated inflammation, attenuated alveolar damage, and improved lung function in a murine model of S. aureus pneumonia. Bacterial proteomic analysis revealed that MCD, at a non-bactericidal concentration, downregulated the toxin synthesis-associated agr and SarA regulatory pathways, inhibited toxin secretion, and induced oxidative stress in S. aureus. Furthermore, MCD directly interacted with Hlα, inhibiting its oligomerization and blocking its hemolytic activity. These findings demonstrate that MCD exerts multi-targeted regulatory effects against S. aureus infection. At a sub-inhibitory concentration, it reduces bacterial pathogenicity both by interfering with the agr/SarA regulatory systems to diminish toxin secretion and by directly neutralizing secreted Hlα toxin, while concurrently alleviating lung injury by suppressing NF-κB signaling-mediated inflammation.