TY - JOUR

T1 - Artificial Siderophores with a Trihydroxamate-DOTAM Scaffold Deliver Iron and Antibiotic Cargo into the Bacterial Pathogen Escherichia coli

AU - Schneider, Isabell

AU - Fetz, Verena

AU - Prochnow, Hans Peter

AU - Brönstrup, Mark

N1 - Funding Information: We would like to acknowledge Dr. Kevin Ferreira and Dr. Philipp Klahn for providing valuable advice on synthetic problems, and Ulrike Beutling for measuring high resolution mass spectra. Open Access funding enabled and organized by Projekt DEAL.

PY - 2023/8/3

Y1 - 2023/8/3

N2 - 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.

AB - 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.

KW - antibiotics

KW - drug discovery

KW - iron

KW - Siderophores

KW - targeted delivery

UR - http://www.scopus.com/inward/record.url?scp=85165267004&partnerID=8YFLogxK

U2 - 10.1002/ijch.202300057

DO - 10.1002/ijch.202300057

M3 - Article

AN - SCOPUS:85165267004

VL - 63

JO - Israel journal of chemistry

JF - Israel journal of chemistry

SN - 0021-2148

IS - 7-8

M1 - e202300057

ER -