扁桃体
抗菌肽
抗菌剂
化学
抗菌活性
两亲性
体内
抗生素
微生物学
抗菌肽
肽
细菌
生物
生物化学
遗传学
生物技术
有机化学
共聚物
聚合物
作者
Josefine Eilsø Nielsen,Morgan A. Alford,Deborah Bow Yue Yung,Natalia Molchanova,John A. Fortkort,Jennifer S Lin,Gill Diamond,Robert E. W. Hancock,Håvard Jenssen,Daniel Pletzer,Reidar Lund,Annelise E. Barron
出处
期刊:ACS Infectious Diseases
[American Chemical Society]
日期:2022-02-17
卷期号:8 (3): 533-545
被引量:38
标识
DOI:10.1021/acsinfecdis.1c00536
摘要
Antimicrobial peptides (AMPs) are promising pharmaceutical candidates for the prevention and treatment of infections caused by multidrug-resistant ESKAPE pathogens, which are responsible for the majority of hospital-acquired infections. Clinical translation of AMPs has been limited, in part by apparent toxicity on systemic dosing and by instability arising from susceptibility to proteolysis. Peptoids (sequence-specific oligo-N-substituted glycines) resist proteolytic digestion and thus are of value as AMP mimics. Only a few natural AMPs such as LL-37 and polymyxin self-assemble in solution; whether antimicrobial peptoids mimic these properties has been unknown. Here, we examine the antibacterial efficacy and dynamic self-assembly in aqueous media of eight peptoid mimics of cationic AMPs designed to self-assemble and two nonassembling controls. These amphipathic peptoids self-assembled in different ways, as determined by small-angle X-ray scattering; some adopt helical bundles, while others form core–shell ellipsoidal or worm-like micelles. Interestingly, many of these peptoid assemblies show promising antibacterial, antibiofilm activity in vitro in media, under host-mimicking conditions and antiabscess activity in vivo. While self-assembly correlated overall with antibacterial efficacy, this correlation was imperfect. Certain self-assembled morphologies seem better-suited for antibacterial activity. In particular, a peptoid exhibiting a high fraction of long, worm-like micelles showed reduced antibacterial, antibiofilm, and antiabscess activity against ESKAPE pathogens compared with peptoids that form ellipsoidal or bundled assemblies. This is the first report of self-assembling peptoid antibacterials with activity against in vivo biofilm-like infections relevant to clinical medicine.
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