Proteomic investigation into the action mechanism of berberine against Streptococcus pyogenes

Berberine is an isoquinoline alkaloid found in many plants. Although berberine is known to possess the antibacterial activity against Streptococcus pyogenes, the mechanism underlying it is not fully understood. In the current study, to investigate the molecular mechanism how berberine exerts its antibacterial effects, quantitative proteomics was conducted to investigate differential expressed proteins in S. pyogenes in response to berberine treatment. KEGG pathways analysis revealed that berberine regulated proteins were mainly involved in carbohydrate metabolism, fatty acid biosynthesis, pyrimidine metabolism, RNA degradation, ribosome, purine metabolism, DNA replication and repair and oxidative phosphorylation pathways. Moreover, we found that berberine induced the accumulation of reactive oxygen species (ROS), whereas inhibition of ROS generation with antioxidant N-acetyl L-cysteine could block the berberine induced antibacterial effects. Collectively, we demonstrated that berberine exerts its antibacterial effects by perturbing carbohydrate metabolism, which therefore generate ROS to damage the DNA, protein and lipids biosynthesis, ultimately trigger cell lethality. These findings provide novel insights into the mechanism of berberine as an antimicrobial drug to control diseases caused by S. pyogenes. Significance: Streptococcus pyogenes is the major cause of invasive bacterial disease in human, which leads to hundreds of million cases annually and over 500,000 deaths due to severe infections. Berberine is an isoquinoline alkaloid from medicinal plants, which possesses a variety of pharmacological effects including antibacterial. In this work, proteomic analysis revealed that berberine affected carbohydrate metabolism, DNA, protein and fatty acid biosynthesis and oxidative phosphorylation pathways in S. pyogenes. And further experimental results showed that berberine exerts its antibacterial effects against Streptococcus pyogenes by stimulated the generation of reactive oxygen species (ROS). These data provide novel insights into the effect of berberine on oxidative stress as an antimicrobial drug.