Synthesis of Cationic Biphen[4, 5]arenes as Biofilm Disruptors

Xinbei Du; Mengke Ma; Yahan Zhang; Xiang Yu; Longming Chen; Han Zhang; Zhao Meng; Xueshun Jia; Junyi Chen; Qingbin Meng; Chunju Li

doi:10.1002/anie.202301857

Synthesis of Cationic Biphen[4, 5]arenes as Biofilm Disruptors

Angew Chem Int Ed Engl. 2023 May 15;62(21):e202301857. doi: 10.1002/anie.202301857. Epub 2023 Apr 14.

Authors

Xinbei Du^{1

2}, Mengke Ma², Yahan Zhang², Xiang Yu^{1

2}, Longming Chen², Han Zhang², Zhao Meng², Xueshun Jia¹, Junyi Chen^{2

3}, Qingbin Meng², Chunju Li³

Affiliations

¹ Department of Chemistry, Center for Supramolecular Chemistry and Catalysis, Shanghai University, Shanghai, 200444, P. R. China.
² State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, P. R. China.
³ Key Laboratory of Inorganic-Organic Hybrid Functional Material Chemistry, Ministry of Education, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, College of Chemistry, Tianjin Normal University, Tianjin, 300387, P. R. China.

PMID: 36929684
DOI: 10.1002/anie.202301857

Abstract

Since bacteria in biofilms are inherently resistant to antibiotics and biofilm-associated infections pose a serious threat to global public health, new therapeutic agents and schemes are urgently needed to meet clinical requirements. Here two quaternary ammonium-functionalized biphen[n]arenes (WBPn, n=4, 5) were designed and synthesized with excellent anti-biofilm potency. Not only could they inhibit the assembly of biofilms, but also eradicate intractable mature biofilms formed by Gram-positive S. aureus and Gram-negative E. coli bacterial strains. Moreover, they could strongly complex a conventional antibiotic, cefazolin sodium (CFZ) with complex stability constants of (7.41±0.29)×10⁴ M^-1 for CFZ/WBP4 and (4.98±0.49)×10³ M^-1 for CFZ/WBP5. Combination of CFZ by WBP4 and WBP5 synergistically enhanced biofilm eradication performance in vitro and statistically improved healing efficacy on E. coli-infected mice models, providing a novel supramolecular strategy for combating biofilm-associated infections.

Keywords: Biofilm Disruptors; Cationic Biphen[n]Arenes; Cefazolin Sodium; Host-Guest Complexation; Synergetic Effect.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Bacterial Agents / pharmacology
Biofilms
Cefazolin
Escherichia coli*
Mice
Microbial Sensitivity Tests
Staphylococcus aureus*

Substances

Anti-Bacterial Agents
Cefazolin