Isabell Schneider, Verena Fetz, Hans-Peter Prochnow, Mark Brönstrup
{"title":"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","authors":"Isabell Schneider, Verena Fetz, Hans-Peter Prochnow, Mark Brönstrup","doi":"10.1002/ijch.202300057","DOIUrl":null,"url":null,"abstract":"<p>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 <b>1</b> to deliver iron into <i>Escherichia coli</i> in a chelation-specific manner was proven by a growth recovery assay. A covalent siderophore-ciprofloxacin conjugate exerted antibiotic effects against <i>E. coli</i>, 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.</p>","PeriodicalId":14686,"journal":{"name":"Israel Journal of Chemistry","volume":null,"pages":null},"PeriodicalIF":2.3000,"publicationDate":"2023-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijch.202300057","citationCount":"0","resultStr":"{\"title\":\"Artificial Siderophores with a Trihydroxamate-DOTAM Scaffold Deliver Iron and Antibiotic Cargo into the Bacterial Pathogen Escherichia coli\",\"authors\":\"Isabell Schneider, Verena Fetz, Hans-Peter Prochnow, Mark Brönstrup\",\"doi\":\"10.1002/ijch.202300057\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>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 <b>1</b> to deliver iron into <i>Escherichia coli</i> in a chelation-specific manner was proven by a growth recovery assay. A covalent siderophore-ciprofloxacin conjugate exerted antibiotic effects against <i>E. coli</i>, 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.</p>\",\"PeriodicalId\":14686,\"journal\":{\"name\":\"Israel Journal of Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2023-07-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijch.202300057\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Israel Journal of Chemistry\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ijch.202300057\",\"RegionNum\":4,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Israel Journal of Chemistry","FirstCategoryId":"92","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ijch.202300057","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
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.
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.