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

Yuanfeng Li; Yin-Zi Piao; Hua Chen; Keqing Shi; Juqin Dai; Siran Wang; Tieli Zhou; Anh-Tuan Le; Yaran Wang; Fan Wu; Rujiang Ma; Linqi Shi; Yong Liu

doi:10.1016/j.bioactmat.2023.04.014

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

Bioact Mater. 2023 Apr 18:27:288-302. doi: 10.1016/j.bioactmat.2023.04.014. eCollection 2023 Sep.

Authors

Yuanfeng Li¹, Yin-Zi Piao², Hua Chen^{2

3}, Keqing Shi¹, Juqin Dai¹, Siran Wang², Tieli Zhou⁴, Anh-Tuan Le⁵, Yaran Wang², Fan Wu³, Rujiang Ma³, Linqi Shi³, Yong Liu^{1

2}

Affiliations

¹ Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
² Wenzhou Institute, University of Chinese Academy of Sciences, Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, 325001, China.
³ Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China.
⁴ Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
⁵ Nano Institute, Phenikaa University, Yen Nghia, Ha Dong, Ha Noi, Viet Nam.

Abstract

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.

Keywords: Biofilms; Biosafety; Dynamic covalent bonds; On-demand drug release; Resistance reversal.