短抗菌肽与模型脂膜之间的功能相互作用。

IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-03 DOI:10.1016/j.bioorg.2024.107939
Lorena Gratino, Marta Gogliettino, Marco Balestrieri, Alessandra Porritiello, Principia Dardano, Bruno Miranda, Rosa Luisa Ambrosio, Monica Ambrosio, Luigi Nicolais, Gianna Palmieri
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引用次数: 0

摘要

抗菌肽(AMPs)因其对病原体具有广谱抗菌活性、低细胞毒性和耐药性等优势特性,被认为是新一代极具吸引力的新型抗生素。虽然它们具有共同的结构特征,而且细菌膜是多肽活性的主要靶点已被广泛证实,但 AMPs 干扰膜的确切机制尚未完全明了。不过,所有提出的作用模式都与 AMPs 与细菌膜上带负电荷的脂质的初步相互作用有关。最近,两种 AMP(RiLK1 和 RiLK3)的结构和功能特征得到了报道。具体来说,这两种肽都是多肽化合物,能以高亲和力结合革兰氏阳性和革兰氏阴性脂质体模型,但它们的作用机制仍然难以捉摸。本文采用不同的方法进一步研究了 RiLK1 和 RiLK3 对模拟原核和真核细胞膜的囊泡的影响。丙烯酰胺或亲油性探针的荧光和淬灭检测表明,多肽主要位于模拟鼠伤寒沙门氏菌和金黄色葡萄球菌的带负电膜的界面上,可能以平行方式定向。此外,RiLK1 和 RiLK3 还会导致羧基荧光素从细菌脂质体中大量渗出,这表明它们能在高剂量下渗透靶膜。相反,这两种肽对细菌靶标的作用浓度接近其 MIC 值时,似乎表现得像细胞穿透肽(CPP)。此外,动态光散射还进一步揭示了抗菌肽对细菌脂质体的作用机制。最终,体外实验表明,RiLK1 和 RiLK3 在较低的微摩尔浓度下对一种耐抗生素的 ESKAPE 病原体具有很强的抑菌作用,使它们成为预防和治疗由这类细菌引起的感染的重要工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Functional interplay between short antimicrobial peptides and model lipid membranes.

Antimicrobial peptides (AMPs) are considered an attractive generation of novel antibiotics due to their advantageous properties such as a broad spectrum of antimicrobial activity against pathogens, low cytotoxicity, and drug resistance. Although they have common structural features and it has been widely demonstrated that bacterial membranes represent the main target of the peptide activity, the exact mechanism underlying the membrane perturbation by AMPs is not fully understood. Nevertheless, all the proposed modes of action implicate the preliminary interaction of AMPs with the negatively charged lipids in bacterial membranes. Recently, the structural and functional characterization of two AMPs, RiLK1 and RiLK3, was reported. Specifically, both peptides were revealed to be multitalented compounds capable of binding Gram-positive and Gram-negative liposome models with high affinity, but their mechanism of action remains elusive. In this paper, the effects of RiLK1 and RiLK3 on vesicles mimicking prokaryotic and eukaryotic cell membranes were further examined by using different approaches. Fluorescence and quenching assays either by acrylamide or lipophilic probes suggested that the peptides were mainly located at the interface of the negatively charged membranes that mimicked those of Salmonella Typhimurium and Staphylococcus aureus, possibly oriented in a parallel manner. Furthermore, RiLK1 and RiLK3 caused a significant leakage of carboxyfluorescein from bacterial liposomes, demonstrating that they can permeabilize the target membranes at high doses. Conversely, both peptides appear to behave like cell penetrating peptides (CPPs) at concentrations near their MIC values evaluated against the bacterial targets. Moreover, Dynamic Light Scattering provided further insights on the mechanisms of antimicrobial peptide against the bacterial liposomes. Conclusively, in vitro experiments indicated that RiLK1 and RiLK3 displayed potent bacteriostatic efficacy at low micromolar concentrations against an antibiotic-resistant ESKAPE pathogen, making them a valuable tool in preventing and treating infections caused by such bacteria.

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来源期刊
Bioorganic Chemistry
Bioorganic Chemistry 生物-生化与分子生物学
CiteScore
9.70
自引率
3.90%
发文量
679
审稿时长
31 days
期刊介绍: Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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