Pathogen-anchoring nano electrosensitizer serves as electro-driven antibiotic adjuvant to revitalize carbapenems activity against NDMs-producing CRE

Infections by Carbapenem-resistant <em>Enterobacteriaceae</em> (CRE) producing New Delhi metallo-β-lactamases (NDMs) that hydrolyze carbapenems, are difficult to treat. Considering the fact of barren antibiotic development pipeline nowadays, revitalize carbapenems efficacy using antibiotic adjuvants represents a promising but as-yet-unrealized tactic in combating NDMs-producing CRE, because of their off-target distributions, weak permeability to the outer membrane (OM) barrier, and limited NDMs-inactivation ability. Here, a pathogen-anchoring nano electrosensitizer, is proposed for serving as electrodynamic therapy (EDT)-activatable antibiotic adjuvant to revitalize meropenem (MEM, a typical carbapenems), through layer-by-layer assembly of platinum nanoclusters (PtNCs), MEM, and maltodextrin (MA). The MA corona of electro-driven nanosensitizer promotes the efficient anchoring of PtNCs and MEM onto the surface of pathogen. Triggered by a square-wave alternating current (AC), MEM is released, PtNCs-based EDT is activated, accompanied by the generation of electro-driven reactive oxygen (ROS) at the bacterial infectious microenvironment. Subsequently, the antibacterial efficacy of MEM is thereby restored against NDMs-producing CRE through the ROS-mediated cascading effect, including the OM destruction, MEM intracellular accumulation, and NDMs inactivation. By the cooperation of MA-mediated pathogen anchoring and EDT-induced dual action, the pathogen-anchoring nano electrosensitizer revitalizes MEM efficacy against clinically isolated NDMs-producing CRE in vitro, and in mice infection model, importantly, also slows down the development of higher-level resistance in NDMs-producing CRE. The pathogen-anchoring nano electrosensitizer can fully play the therapeutic potency of carbapenems, providing a promising approach to tackle NDMs producer-induced infections.