Naringin attenuates Streptococcus agalactiae pathogenicity by inhibiting LuxS/AI-2 quorum sensing and enhances tilapia infection resistance

Streptococcus agalactiae (Group B Streptococcus, GBS) is one of the most harmful pathogens in aquaculture and its virulence is mainly regulated by the LuxS/AI-2 quorum sensing (QS) system. Developing quorum sensing inhibitors (QSIs) targeting the GBS LuxS protein is not prone to inducing drug resistance, which is of great significance for addressing the antimicrobial resistance crisis in aquaculture. This study identified naringin, a potential LuxS inhibitor with anti-GBS virulence activity, from plant-derived natural products through virtual screening combined with experimental verification. The results showed that naringin bound tightly to the entrance of the GBS LuxS active pocket and effectively inhibited luxS gene transcription. This dual action may reduce AI-2 signal molecule synthesis through both potential steric hindrance at the active site and transcriptional inhibition. At sub-inhibitory concentrations, naringin did not inhibit bacterial growth. Instead, it downregulated key virulence genes, significantly suppressed EPS secretion, and disrupted the biofilm barrier, thereby attenuating bacterial virulence. The results of in vivo challenge experiments showed that naringin intervention significantly alleviated histopathological damage in infected hosts and effectively improved the survival rate after infection. This protective effect may be closely associated with the ability of naringin to inhibit the colonization and dissemination of GBS in the host spleen and brain tissues, while downregulating host pro-inflammatory gene expression and upregulating antioxidant gene expression. This study confirmed that naringin can effectively disrupt the GBS LuxS/AI-2 quorum sensing system and exert significant anti-virulence effects. It also provides a new candidate drug and theoretical basis for the green prevention and control of GBS infection in aquaculture.