Nucleotide coordinated polymers, a ROS-based immunomodulatory antimicrobial, doubly kill Pseudomonas aeruginosa biofilms of implant infections

Abstract

Pseudomonas aeruginosa causes high morbidity and mortality in nosocomial infections, and newly approved antibiotics have been declining for decades. A green and universal deprotonation-driven strategy is used to screen the guanylic acid-metal ion coordination polymer nanoparticles (GMC), instead of the failure of binding occurs when specific metal ion participation. We find that the precise pH-dependent oxidase-like activity of GMC-2 orchestrates a duple symphony of immune modulation for Pseudomonas aeruginosa biofilm infections. Specifically, GMC-2-mediated reactive oxygen species (ROS) regulation triggers mitochondrial dysfunction and releases damage-associated molecular patterns, engaging pattern recognition receptors and resulting in endogenous innate immune activation. Meanwhile, GMC-2-triggered ROS generation in a mildly acidic biofilm environment destroys the biofilm, exposing exogenous pathogen-associated molecular patterns. GMC-2 cannot cause resistance for Pseudomonas aeruginosa compared with conventional antibiotics. In an infected implant mouse model, Pseudomonas aeruginosa biofilms were effectively eliminated by GMC-2-mediated triggering of innate and adaptive immunity. These findings provide a universal approach for facilitating the binding of biomolecules with metal ions and highlight the precise ROS-regulating platform plays a critical role in initiating endogenous and exogenous immune activation targeted for bacterial biofilm infection.