Exogenous adenosine and/or guanosine enhances tetracycline sensitivity of persister cells

Vibrio splendidus is an opportunistic pathogen, its pathogenicity continues to be a major aquaculture disease infection problem in many parts of the world. Bacteria can form dormant and persister cells, which may be responsible for the difficulty in treating latent infections. Bacterial persister cells are a small subpopulation with high phenotypic heterogeneity that have the ability to persist in response to high concentrations of antibiotics. In our previous work, we have confirmed tetracycline could induce V. splendidus AJ01 persister cells formation. Here, we show that exogenous adenosine and/or guanosine supply restores susceptibility of AJ01 persister cells to tetracycline, leading to effective killing of this persist subpopulation upon wake-up. Mechanistically, exogenous adenosine and/or guanosine promotes the intracellular ATP level, reduces percentage of cells with protein aggresomes, and destroys membrane stability. In addition, when cells were exposed to tetracycline, we found that cells with small nucleocytoplasmic ratio is easy to survive. Overall, our results support that exogenous adenosine or guanosine could be an effective strategy for treating infections with antibiotic-persist bacteria via regulating persisters cells formation.