Multi-omics reveals an extracellular vesicles-mediated susceptibility: Conferring carbenicillin resistance while compromising copper tolerance in Vibrio parahaemolyticus.

Extracellular vesicles (EVs) serve as pivotal mediators of bacterial intercellular communication, facilitating survival under diverse environmental hostilities. However, the regulatory landscape of EVs under the complex interplay of antibiotic and heavy metal co-stress remains an enigma. Here, we integrated multi-omics analyses to decipher the impact of EVs derived from a multidrug-resistant Vibrio parahaemolyticus strain (VP38) on a susceptible strain (VP35) under separated or combined stress of carbenicillin (CARB) and copper (Cu). Unexpectedly, the EV-mediated effects were stress-type specific: they promoted survival under CARB stress but markedly reduced viability under Cu exposure. Mechanistically, transcriptomic analysis showed that EVs uptake was associated with transcriptional reprogramming in the recipient strain, including downregulation of copper efflux genes (e.g., cusB/R) and iron acquisition genes (e.g., TonB-dependent receptors). This expression pattern suggests a possible disturbance in intracellular ion homeostasis and may contribute to increased susceptibility to heavy metal stress. These findings support a context-dependent defense-burden model of EV-mediated stress adaptation under combined antibiotic and metal stress. This study not only advances our understanding of bacterial social behaviors but also highlights EV-induced metabolic interference as a potential therapeutic strategy against resistant pathogens in aquaculture.