Adjuvant-like biomimetic nanovesicles combat New Delhi metallo-β-lactamases (NDMs) producing superbugs infections

Abstract Infections by NDMs-producing superbugs that hydrolyze nearly all available antibiotics, including the last-resort antimicrobials, carbapenems, are difficult to treat. Antibiotic-adjuvant combination therapy is a promising tactic for tackling the antimicrobial resistance of superbugs. However, lacking effective but safe adjuvants and the off-target toxicity of drugs remain the major challenges for combined therapy to achieve the maximum benefits. Herein, an adjuvant-like biomimetic nanovesicle was developed by ultrasonically storing meropenem-loaded polyamidoamine (PAMAM) dendrimer into platelet membrane vesicles (PMVs), which integrated potent adjuvant activity, high drugs loading yields, pathogen targeting and site-specific drug release properties into a vesicle. Leveraging natural pathogen affinity and inherent pH-responsive property of PMVs, the nanovesicles precisely deliver PAMAM (a potent but safe antibiotic adjuvant proved in this study) and meropenem (a typical carbapenem) to bacterial infection sites, simultaneously achieving inflammatory microenvironment-powered drugs rapid release. Meanwhile, the biocompatible PAMAM shows strong adjuvant activity via unique dual mechanisms: 1) the polymer penetrates bacterial membrane and enhances membrane permeability, then facilitates the transport of meropenem. 2) after membrane penetration, PAMAM inhibits NDMs activity by depriving zinc ions of NDMs active sites, thus preventing meropenem from hydrolyzation. Consequently, the nanovesicles boosted meropenem efficacy against clinical NDMs-producing E.coli both in vitro and in vivo, importantly, also minimized off-target toxicity of drugs. Amazingly, the nanosystem reduced the higher-level resistance evolution in the NDMs-producing E.coli. Overall this study helps to address major hurdles in the management of NDMs-producing superbugs infections, enabling repurposing drugs as effective antibiotics while maintaining safety.