ABSTRACT
OBJECTIVES: Streptococcus pneumoniae (S. pneumoniae) is an important commensal and pathogenic bacterium responsible for pneumonia, meningitis and other invasive diseases. Pneumolysin (PLY) is the major virulence factor that contributes significantly to the interaction between S. pneumoniae and the host. KEY FINDINGS: In this study, the results of antibacterial analysis, the haemolysis test and the Western blotting assay showed that acacetin inhibited PLY-mediated pore-forming activity caused by S. pneumoniae culture precipitates and purified PLY without anti-S. pneumoniae activity. In addition, acacetin treatment inhibited PLY oligomerization without affecting the expression of PLY in S. pneumoniae culture supernatants. Live/dead cells and cytotoxicity assays suggested that acacetin significantly enhanced the survival rate of injured cells by inhibiting the biological toxicity of PLY without cytotoxicity in the coculture system. The in vivo mouse model of S. pneumoniae infection further demonstrated that acacetin treatment could significantly reduce the levels of inflammatory factors (INF-γ and IL-ß) in bronchoalveolar lavage fluid (BALF) and alleviate the pathological damage of lung injury. CONCLUSIONS: Taken together, the results presented in this study indicated that acacetin inhibited the pore-forming activity of PLY and reduced the virulence of S. pneumoniae in vivo and in vitro, which may provide a leading compound for the treatment of S. pneumoniae infection.
Subject(s)
Anti-Bacterial Agents/pharmacology , Flavones/pharmacology , Lung/drug effects , Pneumonia, Pneumococcal/drug therapy , Streptococcus pneumoniae/drug effects , Streptolysins/antagonists & inhibitors , A549 Cells , Animals , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/metabolism , Bronchoalveolar Lavage Fluid/immunology , Disease Models, Animal , Female , Hemolysis/drug effects , Host-Pathogen Interactions , Humans , Inflammation Mediators/metabolism , Interferon-gamma/metabolism , Interleukin-1beta/metabolism , Lung/immunology , Lung/metabolism , Lung/microbiology , Mice, Inbred BALB C , Microbial Viability/drug effects , Pneumonia, Pneumococcal/immunology , Pneumonia, Pneumococcal/metabolism , Pneumonia, Pneumococcal/microbiology , Streptococcus pneumoniae/metabolism , Streptococcus pneumoniae/pathogenicity , Streptolysins/metabolism , VirulenceABSTRACT
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.
