Zscherp, Robert, Coetzee, Janetta, Vornweg, Johannes ORCID: 0000-0002-1457-0173, Grunenberg, Joerg, Herrmann, Jennifer, Mueller, Rolf and Klahn, Philipp ORCID: 0000-0003-4713-2345 (2021). Biomimetic enterobactin analogue mediates iron-uptake and cargo transport into E. coli and P. aeruginosa. Chem. Sci., 12 (30). S. 10179 - 10192. CAMBRIDGE: ROYAL SOC CHEMISTRY. ISSN 2041-6539

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Abstract

The design, synthesis and biological evaluation of the artificial enterobactin analogue Ent(KL) and several fluorophore-conjugates thereof are described. Ent(KL) provides an attachment point for cargos such as fluorophores or antimicrobial payloads. Corresponding conjugates are recognized by outer membrane siderophore receptors of Gram-negative pathogens and retain the natural hydrolyzability of the tris-lactone backbone. Initial density-functional theory (DFT) calculations of the free energies of solvation (Delta G(sol)) and relaxed Fe-O force constants of the corresponding [Fe-Ent(KL)](3-) complexes indicated a similar iron binding constant compared to natural enterobactin (Ent). The synthesis of Ent(KL) was achieved via an iterative assembly based on a 3-hydroxylysine building block over 14 steps with an overall yield of 3%. A series of growth recovery assays under iron-limiting conditions with Escherichia coli and Pseudomonas aeruginosa mutant strains that are defective in natural siderophore synthesis revealed a potent concentration-dependent growth promoting effect of Ent(KL) similar to natural Ent. Additionally, four cargo-conjugates differing in molecular size were able to restore growth of E. coli indicating an uptake into the cytosol. P. aeruginosa displayed a stronger uptake promiscuity as six different cargo-conjugates were found to restore growth under iron-limiting conditions. Imaging studies utilizing BODIPYFL-conjugates, demonstrated the ability of Ent(KL) to overcome the Gram-negative outer membrane permeability barrier and thus deliver molecular cargos via the bacterial iron transport machinery of E. coli and P. aeruginosa.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Zscherp, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coetzee, JanettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vornweg, JohannesUNSPECIFIEDorcid.org/0000-0002-1457-0173UNSPECIFIED
Grunenberg, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herrmann, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klahn, PhilippUNSPECIFIEDorcid.org/0000-0003-4713-2345UNSPECIFIED
URN: urn:nbn:de:hbz:38-587495
DOI: 10.1039/d1sc02084f
Journal or Publication Title: Chem. Sci.
Volume: 12
Number: 30
Page Range: S. 10179 - 10192
Date: 2021
Publisher: ROYAL SOC CHEMISTRY
Place of Publication: CAMBRIDGE
ISSN: 2041-6539
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INFECTIOUS-DISEASES SOCIETY; BETA-LACTAM ANTIBIOTICS; ESCHERICHIA-COLI; CATECHOLATE-SIDEROPHORE; FERRIC ENTEROBACTIN; PSEUDOMONAS-AERUGINOSA; ANTIBACTERIAL ACTIVITY; BACTERIAL SIDEROPHORES; COORDINATION CHEMISTRY; CRYSTAL-STRUCTUREMultiple languages
Chemistry, MultidisciplinaryMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/58749

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