Dynamic covalent nano-networks comprising antibiotics and polyphenols orchestrate bacterial drug resistance reversal and inflammation alleviation.

New antimicrobial strategies are urgently needed to meet the challenges posed by the emergence of drug-resistant bacteria and bacterial biofilms. This work reports the facile synthesis of antimicrobial dynamic covalent nano-networks (aDCNs) composing antibiotics bearing multiple primary amines, polyphenols, and a cross-linker acylphenylboronic acid. Mechanistically, the iminoboronate bond drives the formation of aDCNs, facilitates their stability, and renders them highly responsive to stimuli, such as low pH and high H2O2 levels. Besides, the representative A1B1C1 networks, composed of polymyxin B1(A1), 2-formylphenylboronic acid (B1), and quercetin (C1), inhibit biofilm formation of drug-resistant Escherichia coli, eliminate the mature biofilms, alleviate macrophage inflammation, and minimize the side effects of free polymyxins. Excellent bacterial eradication and inflammation amelioration efficiency of A1B1C1 networks are also observed in a peritoneal infection model. The facile synthesis, excellent antimicrobial performance, and biocompatibility of these aDCNs potentiate them as a much-needed alternative in current antimicrobial pipelines.

GOx-encapsulated iron-phenolic networks power catalytic cascade to eradicate bacterial biofilms.

Bacterial biofilms, especially ones caused by multi-drug resistant strains, are increasingly posing a significant threat to human health. Inspired by nature, we report the fabrication of glucose oxidase-loaded iron-phenolic networks that can power the cascade reaction to generate free radicals to eradicate bacterial biofilms. A soft template, sodium deoxycholate, is employed to guarantee glucose oxidase activity during encapsulation, yielding the porous nanocomplexes after removing the template. The porous nature of nanocomplexes, characterized via transmission electron microscopy, N2 adsorption isotherms, and thermogravimetric analysis, facilitates the diffusion of substrates and products during the cascade reaction and protects glucose oxidase from protease attack. Our optimized nanocomplexes (Fe-GA/GOx) could efficiently kill drug-resistant ESKAPE pathogens, including the clinically isolated strains and eradicate their biofilms. In this regard, Fe-GA/GOx could induce over 90% of the biomass of Klebsiella pneumoniae and Staphylococcus aureus biofilms. In the murine peritonitis infection model induced by Staphylococcus aureus and pneumonia model induced by Klebsiella pneumoniae, our Fe-GA/GOx nanocomplexes could efficiently eradicate the bacteria (over 3-log reduction in colony-forming units) and alleviate the inflammatory response without notable side effects on normal tissues. Therefore, our strategy may provide an efficient alternative treatment to combat bacterial biofilms and address the emergence of drug resistance.