School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 637459, Singapore.
Bioinformatics Institute, A*STAR, 30 Biopolis Street, Matrix, 138671, Singapore; Singapore Eye Research Institute, 169856, Singapore.
Biomaterials. 2023 Mar;294:122004. doi: 10.1016/j.biomaterials.2023.122004. Epub 2023 Jan 13.
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.
需要新的抗生素来对抗革兰氏阴性菌，尤其是多药耐药（MDR）和表型耐药的生物膜物种。目前，只有序列定义的α-肽（如多粘菌素 B）可以选择性地靶向革兰氏阴性菌的脂多糖。我们发现一种无序列定义的共聚物对包括其生物膜形式在内的 MDR 革兰氏阴性菌具有良好的活性。具有受控 N 端疏水性的锥形块状共 β-肽（#4）通过静电和氢键相互作用通过其骨架与革兰氏阴性菌的脂多糖强烈相互作用，但不与革兰氏阳性菌和哺乳动物细胞膜相互作用，因此该共聚物对后两种细胞类型无毒。新型#4 共 β-肽在体外和小鼠生物膜伤口感染模型中均具有选择性杀伤革兰氏阴性菌的低细胞毒性。这种策略为针对 MDR 和生物膜物种的革兰氏阴性选择性抗菌肽模拟物的设计提供了新概念。
