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

• Main Authors: Si. Zhangyong, Li, Jianguo, Ruan, Lin, Reghu, Sheethal, Ooi, Ying Jie, Li, Peng, Zhu, Yabin, Hammond, Paula T., Verma, Chandra S., Bazan, Guillermo C., Pethe, Kevin, Chan-Park, Mary B.
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2023
• Subjects: Science::Biological sciences::Microbiology; Engineering::Bioengineering; Beta-Peptide; Antimicrobial Peptides
• Online Access: https://hdl.handle.net/10356/164620
• Institution: Nanyang Technological University

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.