Enzyme-Triggered Polyelectrolyte Complex for Responsive Delivery of α-Helical Polypeptides to Optimize Antibacterial Therapy

Biomacromolecules. 2024 May 13;25(5):3112-3121. doi: 10.1021/acs.biomac.4c00206. Epub 2024 Apr 23.

Abstract

Responsive nanomaterials hold significant promise in the treatment of bacterial infections by recognizing internal or external stimuli to achieve stimuli-responsive behavior. In this study, we present an enzyme-responsive polyelectrolyte complex micelles (PTPMN) with α-helical cationic polypeptide as a coacervate-core for the treatment of Escherichia coli (E. coli) infection. The complex was constructed through electrostatic interaction between cationic poly(glutamic acid) derivatives and phosphorylation-modified poly(ethylene glycol)-b-poly(tyrosine) (PEG-b-PPTyr) by directly dissolving them in aqueous solution. The cationic polypeptide adopted α-helical structure and demonstrated excellent broad-spectrum antibacterial activity against both Gram-negative and Gram-positive bacteria, with a minimum inhibitory concentration (MIC) as low as 12.5 μg mL-1 against E. coli. By complexing with anionic PEG-b-PPTyr, the obtained complex formed β-sheet structures and exhibited good biocompatibility and low hemolysis. When incubated in a bacterial environment, the complex cleaved its phosphate groups triggered by phosphatases secreted by bacteria, exposing the highly α-helical conformation and restoring its effective bactericidal ability. In vivo experiments confirmed accelerated healing in E. coli-infected wounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents* / administration & dosage
  • Anti-Bacterial Agents* / chemistry
  • Anti-Bacterial Agents* / pharmacology
  • Escherichia coli Infections / drug therapy
  • Escherichia coli* / drug effects
  • Hemolysis / drug effects
  • Humans
  • Mice
  • Micelles
  • Microbial Sensitivity Tests
  • Peptides / chemistry
  • Peptides / pharmacology
  • Polyelectrolytes / chemistry
  • Polyelectrolytes / pharmacology
  • Polyethylene Glycols / chemistry
  • Polyethylene Glycols / pharmacology
  • Polyglutamic Acid / analogs & derivatives
  • Polyglutamic Acid / chemistry
  • Polyglutamic Acid / pharmacology
  • Protein Conformation, alpha-Helical

Substances

  • Anti-Bacterial Agents
  • Polyelectrolytes
  • Peptides
  • Micelles
  • Polyethylene Glycols
  • Polyglutamic Acid