Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Zscherp, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Coetzee, Janetta UNSPECIFIED UNSPECIFIED UNSPECIFIED Vornweg, Johannes UNSPECIFIED orcid.org/0000-0002-1457-0173 UNSPECIFIED Grunenberg, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Herrmann, Jennifer UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Klahn, Philipp UNSPECIFIED orcid.org/0000-0003-4713-2345 UNSPECIFIED
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:	Keywords Language INFECTIOUS-DISEASES SOCIETY; BETA-LACTAM ANTIBIOTICS; ESCHERICHIA-COLI; CATECHOLATE-SIDEROPHORE; FERRIC ENTEROBACTIN; PSEUDOMONAS-AERUGINOSA; ANTIBACTERIAL ACTIVITY; BACTERIAL SIDEROPHORES; COORDINATION CHEMISTRY; CRYSTAL-STRUCTURE Multiple languages Chemistry, Multidisciplinary Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58749