Designer co-beta-peptide copolymer selectively targets resistant and biofilm Gram-negative bacteria

Zhangyong Si, Jianguo Li, Lin Ruan, Sheethal Reghu, Ying Jie Ooi, Peng Li, Yabin Zhu, Paula T. Hammond, Chandra S. Verma, Guillermo C. Bazan, Kevin Pethe, Mary B. Chan-Park

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

New antimicrobials are urgently needed to combat Gram-negative bacteria, particularly multi-drug resistant (MDR) and phenotypically resistant biofilm species. At present, only sequence-defined alpha-peptides (e.g. polymyxin B) can selectively target Gram-negative bacterial lipopolysaccharides. We show that a copolymer, without a defined sequence, shows good potency against MDR Gram-negative bacteria including its biofilm form. The tapered blocky co-beta-peptide with controlled N-terminal hydrophobicity (#4) has strong interaction with the Gram-negative bacterial lipopolysaccharides via its backbone through electrostatic and hydrogen bonding interactions but not the Gram-positive bacterial and mammalian cell membranes so that this copolymer is non-toxic to these two latter cell types. The new #4 co-beta-peptide selectively kills Gram-negative bacteria with low cytotoxicity both in vitro and in a mouse biofilm wound infection model. This strategy provides a new concept for the design of Gram-negative selective antimicrobial peptidomimetics against MDR and biofilm species.

Original languageEnglish
Article number122004
JournalBiomaterials
Volume294
DOIs
StatePublished - Mar 2023

Keywords

  • Antimicrobial peptides
  • Beta-peptide
  • Biofilm
  • Gram-selective
  • Lipopolysaccharide
  • Persisters

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