Accumulation of Histidine Reduce the Susceptibility of <scp> <i>Vibrio splendidus</i> </scp> Persister Cells to Tetracycline

Vibrio splendidus is an opportunistic pathogen widely distributed in marine environments, animal tissues and seabed sediments. It can infect various marine animals, resulting in high mortality and substantial economic losses. Exposure to high concentrations of tetracycline induces V. splendidus to form persister cells, which exhibit tolerance to multiple classes of antibiotics and pose a serious threat to aquaculture by promoting disease outbreaks. Previous studies have suggested that metabolic regulation is a key mechanism for maintaining the dormant and low-energy state of persister cells. In this study, we found that the accumulation of histidine-derived metabolites significantly reduced the susceptibility of V. splendidus to tetracycline. Transcriptomic analysis revealed a marked upregulation of genes involved in histidine metabolism and exogenous supplementation of histidine significantly increased the proportion of persister cells, suggesting that histidine plays a promotive role in persister formation. Furthermore, histidine enhanced the membrane potential and upregulated the expression of the efflux pump gene tolC, thereby contributing to the formation of tetracycline-induced persister cells. These findings reveal a previously unrecognized role of histidine metabolism in antibiotic tolerance and provide a theoretical basis for understanding persister cell formation in V. splendidus.