具有三羟肟酸盐-DOTAM支架的人工Siderophores将铁和抗生素货物输送到细菌病原体大肠杆菌中

IF 2.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Israel Journal of Chemistry Pub Date : 2023-07-19 DOI:10.1002/ijch.202300057
Isabell Schneider, Verena Fetz, Hans-Peter Prochnow, Mark Brönstrup
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引用次数: 0

摘要

耐多药革兰氏阴性菌感染是一种无声的大流行威胁,在全球范围内正在增加。阻碍开发针对革兰氏阴性菌的有效抗生素的一个主要技术和科学障碍是革兰氏阴性菌外膜的渗透性低,这阻止了大多数小分子进入细胞。这可以通过利用载药人工铁载体的特洛伊木马策略靶向病原体的活性铁运输系统来克服。虽然我们在之前的工作中使用儿茶酚作为铁结合基序,但本研究报告了用三个羟酸臂取代的DOTAM支架的铁载体的设计、合成和表征,从而实现铁的六配位。它们的铁螯合能力被比色法证明,化合物1以螯合特异性方式将铁传递到大肠杆菌的能力被生长恢复试验证明。一种共价铁载体-环丙沙星缀合物对大肠杆菌具有抗生素作用,尽管其效力低于游离药物。该研究证实了羟基甲酸酯结合物的人工DOTAM铁载体可以作为细菌特洛伊木马的支架。这一贡献是为了纪念我的导师赫尔穆特·施瓦茨,这与我和他一起工作的两个主题相呼应:羟胺,我第一篇论文的主题,以及铁离子的迷人特性,我在博士论文中研究的气相,成为我们当前抗感染化学生物学研究的核心课题。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Artificial Siderophores with a Trihydroxamate-DOTAM Scaffold Deliver Iron and Antibiotic Cargo into the Bacterial Pathogen Escherichia coli

Infections with multidrug-resistant Gram-negative bacteria constitute a silent pandemic threat that is increasing globally. A major technical and scientific hurdle hampering the development of efficient antibiotics against Gram-negative species is the low permeability of their outer membrane that prevents the entry of most small molecules into the cells. This can be overcome by targeting active iron transport systems of the pathogens in a Trojan-Horse strategy that makes use of drug-loaded artificial siderophores. While we utilized catechols as iron-binding motifs in previous work, this study reports the design, synthesis and characterization of siderophores with a DOTAM scaffold that was substituted with three hydroxamate arms allowing for a hexacoordination of iron. Their iron-chelating capabilities were shown colorimetrically, and the ability of compound 1 to deliver iron into Escherichia coli in a chelation-specific manner was proven by a growth recovery assay. A covalent siderophore-ciprofloxacin conjugate exerted antibiotic effects against E. coli, albeit it was less potent than the free drug. The study qualifies artificial DOTAM siderophores with hydroxamate binders as scaffolds for bacterial Trojan Horses. This contribution for honoring my mentor Helmut Schwarz echoes two motifs of my work with him: Hydroxylamin, the topic of my first paper ever, and the fascinating properties of iron ions, studied in the gas phase during my Ph.D. Thesis, became a core subject of our current chemical biology research on antiinfectives.

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来源期刊
Israel Journal of Chemistry
Israel Journal of Chemistry 化学-化学综合
CiteScore
6.20
自引率
0.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: The fledgling State of Israel began to publish its scientific activity in 1951 under the general heading of Bulletin of the Research Council of Israel, which quickly split into sections to accommodate various fields in the growing academic community. In 1963, the Bulletin ceased publication and independent journals were born, with Section A becoming the new Israel Journal of Chemistry. The Israel Journal of Chemistry is the official journal of the Israel Chemical Society. Effective from Volume 50 (2010) it is published by Wiley-VCH. The Israel Journal of Chemistry is an international and peer-reviewed publication forum for Special Issues on timely research topics in all fields of chemistry: from biochemistry through organic and inorganic chemistry to polymer, physical and theoretical chemistry, including all interdisciplinary topics. Each topical issue is edited by one or several Guest Editors and primarily contains invited Review articles. Communications and Full Papers may be published occasionally, if they fit with the quality standards of the journal. The publication language is English and the journal is published twelve times a year.
期刊最新文献
Cover Picture: (Isr. J. Chem. 8-9/2024) Special Issue on RNA-Based Catalysts that Revolutionized the Discovery of Bioactive Peptides Hexagonal and Trigonal Quasiperiodic Tilings Breaking the Degeneracy of Sense Codons – How Far Can We Go? Cover Picture: (Isr. J. Chem. 6-7/2024)
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