Arginine‐Enhanced Antimicrobial Activity of Nanozymes against Gram‐Negative Bacteria

The continuous reduction of clinically available antibiotics has made it imperative to exploit more effective antimicrobial therapies, especially for difficult‐to‐treat Gram‐negative pathogens. Herein, it is shown that the combination of an antimicrobial nanozyme with the clinically compatible basic amino acid L‐arginine affords a potent treatment for infections with Gram‐negative pathogens. In particular, the antimicrobial activity of the antimicrobial nanozyme is dramatically increased by ≈1000‐fold after L‐arginine stimulation. Specifically, the combination therapy enhances bacterial outer and inner membrane permeability and promotes intracellular reactive oxygen species (ROS) generation. Moreover, the metabolomic and transcriptomic results reveal that combination treatment leads to the increased ROS‐mediated damage by inhibiting the tricarboxylic acid cycle and oxidative phosphorylation, thereby inducing an imbalance of the antioxidant and oxidant systems. Importantly, L‐arginine dramatically significantly accelerates the healing of infected wounds in mouse models of multidrug‐resistant peritonitis‐sepsis and skin wound infection. Overall, this work demonstrates a novel synergistic antibacterial strategy by combining the antimicrobial nanozymes with L‐arginine, which substantively facilitates the nanozyme‐mediated killing of pathogens by promoting ROS production. It is reported that L‐arginine exhibits potent synergistic antibacterial activity with nanozymes. The combination therapy leads to increased ROS‐mediated membrane damage by inhibiting the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), adenosine triphosphate (ATP) synthesis, and the bacterial antioxidant system. The discovery of L‐arginine as a powerful adjunctive agent in combating bacterial infections holds significant implications.