Stevioside curbs Streptococcus pneumoniae infection via inhibiting capsule biosynthesis

Streptococcus pneumoniae (S. pneumoniae) remains a predominant cause of high morbidity and mortality in childhood and the elderly, despite the widespread pneumococcal conjugate vaccines (PCVs) vaccination through the world. The critical role of capsule in the pathogenicity of S. pneumoniae makes it an attractive drug target for alternative strategies to combat antibiotic-resistant and non-vaccine serotype infections. Here, we identified the natural compound molecule stevioside as an effective capsule inhibitor that reduces the biosynthesis of capsular polysaccharide through interfering with pyruvate metabolism and subsequent disruption of bacterial NAD + /NADH redox balance and energy generation. In vitro, the compound significantly sensitized streptococci to stress attacks and the killing of antibacterial peptides (AMPs). Meanwhile, capsule-mediated resistance to complement deposition, epithelial adherence and phagocytosis were all remarkably attenuated by stevioside. In vivo, stevioside treatment systematically protected mice from lethal streptococcal pneumoniae, as evident by an increased survival rate, alleviated pathological damage and inflammation level. Overall, the study provides stevioside as a promising lead compound for the further development of chemical capsule inhibitors aimed at curbing S. pneumoniae infections, and reveals a novel strategy for the discovery of S. pneumoniae capsule inhibitors based on pyruvate metabolism pathways.