Exploring Fe(III) coordination and membrane interaction of a siderophore-peptide conjugate: Enhancing synergistically the antimicrobial activity

IF 3.8 2区 化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Rosa Bellavita , Simone Braccia , Lorenzo Emiliano Imbò , Paolo Grieco , Stefania Galdiero , Gabriella D'Auria , Annarita Falanga , Lucia Falcigno
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Abstract

Many microbes produce siderophores, which are extremely potent weapons capable of stealing iron ions from human tissues, fluids and cells and transferring them into bacteria through their appropriate porins. We have recently designed a multi-block molecule, each block having a dedicated role. The first component is an antimicrobial peptide, whose good effectiveness against some bacterial strains was gradually improved through interactive sequence modifications. Connected to this block is a flexible bio-band, also optimized in length, which terminates in a hydroxyamide unit, a strong metal binder. Thus, the whole molecule brings together two pieces that work synergistically to fight infection. To understand if the peptide unit, although modified with a long tail, preserves the structure and therefore the antimicrobial activity, and to characterize the mechanism of interaction with bio-membrane models mimicking Gram-negative membranes, we performed a set of fluorescence-based experiments and circular dichroism studies, which further supported our design of a combination of two different entities working synergistically. The chelating activity and iron(III) binding of the peptide was confirmed by iron(III) paramagnetic NMR analyses, and through a competitive assay with ethylenediamine-tetra acetic acid by ultraviolet–visible spectroscopy. The complexation parameters, the Michaelis constant K, and the number of sites n, evaluated with spectrophotometric techniques are confirmed by Fe(III) paramagnetic NMR analyses here reported. In conclusion, we showed that the coupling of antimicrobial capabilities with iron-trapping capabilities works well in the treatment of infectious diseases caused by Gram-negative pathogens.

Abstract Image

探索苷酸-肽共轭物的铁(III)配位和膜相互作用:协同增强抗菌活性。
许多微生物都会产生嗜苷酸盐,这是一种极其有效的武器,能够从人体组织、体液和细胞中窃取铁离子,并通过相应的孔隙将其转移到细菌体内。我们最近设计了一种多区块分子,每个区块都有专门的作用。第一部分是抗菌肽,通过交互式序列修改,逐步提高了其对某些细菌菌株的良好效果。与该肽段相连的是一条柔性生物带,其长度也经过优化,以羟酰胺单元为末端,是一种强金属粘合剂。因此,整个分子由两部分组成,协同作用,共同抗感染。为了了解肽单元虽然经过长尾修饰,但是否保留了结构,从而保留了抗菌活性,并确定其与模拟革兰氏阴性膜的生物膜模型的相互作用机制,我们进行了一系列基于荧光的实验和圆二色性研究,这进一步支持了我们设计的两种不同实体协同作用的组合。铁(III)顺磁性核磁共振分析证实了该多肽的螯合活性和铁(III)结合力,紫外可见光谱也证实了它与乙二胺四乙酸的竞争性分析。此处报告的铁(III)顺磁核磁共振分析证实了分光光度法评估的络合参数、迈克尔斯常数 K 和位点数 n。总之,我们的研究表明,将抗菌能力与铁捕获能力结合起来,可以很好地治疗由革兰氏阴性病原体引起的传染病。
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来源期刊
Journal of Inorganic Biochemistry
Journal of Inorganic Biochemistry 生物-生化与分子生物学
CiteScore
7.00
自引率
10.30%
发文量
336
审稿时长
41 days
期刊介绍: The Journal of Inorganic Biochemistry is an established international forum for research in all aspects of Biological Inorganic Chemistry. Original papers of a high scientific level are published in the form of Articles (full length papers), Short Communications, Focused Reviews and Bioinorganic Methods. Topics include: the chemistry, structure and function of metalloenzymes; the interaction of inorganic ions and molecules with proteins and nucleic acids; the synthesis and properties of coordination complexes of biological interest including both structural and functional model systems; the function of metal- containing systems in the regulation of gene expression; the role of metals in medicine; the application of spectroscopic methods to determine the structure of metallobiomolecules; the preparation and characterization of metal-based biomaterials; and related systems. The emphasis of the Journal is on the structure and mechanism of action of metallobiomolecules.
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