Development of novel nanoantibiotics using an outer membrane vesicle-based drug efflux mechanism

Conventionally used antibiotics are present in low concentrations at the infection site and require multiple administrations to sustain a continuous bactericidal effect, which not only increases their systemic toxicity but also results in bacterial drug resistance. In this study, we first identified an interesting drug resistance mechanism mediated by bacterial outer membrane vesicles (OMVs) and then designed novel antibiotic-loaded OMVs using this mechanism. We show that these antibiotic-loaded OMVs can effectively enter and kill pathogenic bacteria in vitro. In a mouse model of intestinal bacterial infection, one low-dose oral administration of antibiotic-loaded OMVs showed that the drug was retained in the intestine for 36 h, and no systemic spread was detected 12 h after drug administration. The antibiotic-loaded OMVs significantly reduced the bacterial load in the small intestine and feces of infected mice. Safety experiments confirmed that the antibiotic-loaded OMVs had excellent biocompatibility. This study extends the application range of OMVs and provides new ideas for the development of antibacterial drugs. We first identified an interesting drug-resistance mechanism mediated by bacterial outer membrane vesicles (OMVs) and then designed novel antibiotic-loaded OMVs (antibiotic-OMVs) using this mechanism to protect against intestinal bacterial infection. [Display omitted] •Bacteria excrete large amounts of antibiotic-loaded vesicles through high efflux pump expression and OMV secretion.•OMVs effectively load antibiotics and improve antibiotic stability.•Antibiotic-loaded OMV exert passive and active bactericidal effects through drug release and bacterial invasion.•Antibiotic-loaded OMVs have excellent biocompatibility.•Antibiotic-loaded OMVs can effectively protect against intestinal bacterial infections with oral administration.