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

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

Biomaterials

10.1016/j.biomaterials.2023.122004

http://dx.doi.org/10.1016/j.biomaterials.2023.122004

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

13 January 2023

Si, Z., Li, J., Ruan, L., Reghu, S., Ooi, Y. J., Li, P., Zhu, Y., Hammond, P. T., Verma, C. S., Bazan, G. C., Pethe, K., & Chan-Park, M. B. (2023). Designer co-beta-peptide copolymer selectively targets resistant and biofilm Gram-negative bacteria. Biomaterials, 294, 122004. https://doi.org/10.1016/j.biomaterials.2023.122004

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.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

This research / project is supported by the Ministry of Education - AcRF Tier 3
Grant Reference no. : MOE2018-T3-1-003

This research / project is supported by the Ministry of Education - AcRF Tier 3
Grant Reference no. : MOE2013-T3-1-002

This research / project is supported by the A*STAR - Wound Care Innovation for the Tropics IAF-PP (HBMS Domain)
Grant Reference no. : H17/01/a0/0M9

This research / project is supported by the A*STAR - RIE2020 Advanced Manufacturing and Engineering (AME) IAP-PP Specialty Chemicals Programme
Grant Reference no. : A1786a0032

This research / project is supported by the A*STAR - Career Development Award
Grant Reference no. : 202D8155

ASTAR - H17/01/a0/010, IAF111213C.

https://oar.a-star.edu.sg/communities-collections/articles/20676

0142-9612

Bioinformatics Institute