Escherichia coli outer membrane vesicles encapsulating small molecule antibiotics improve drug function by facilitating transport

The development of novel antimicrobial agents that are effective against Gram-negative bacteria is hindered by the dual membrane cell wall structure of these bacteria. To reach their intracellular targets, most antibiotics must therefore pass through protein channels called porins; however, a common mechanism of acquired resistance is decreased expression of these proteins. Inspired by the ability of outer membrane vesicles (OMVs) to deliver cargo to the bacterial cytosol, we hypothesized that encapsulation of small molecule antibiotics within OMVs would improve the activity of the drugs by facilitating uptake. To test this, we investigated the ability of antibiotic- encapsulated OMVs to inhibit the growth of both Gram-negative and Gram-positive bacteria, including multidrug-resistant clinical isolates. We also demonstrated that this mechanism of delivery does not require porin expression. Together, our results demonstrate the potential of OMVs as novel antibiotic delivery vehicles to treat antibiotic-resistant bacterial infections.