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Biomimetic enterobactin analogue mediates iron-uptake and cargo transport into E. coli and P. aeruginosa

The design, synthesis and biological evaluation of the artificial enterobactin analogue EntKL and several fluorophore-conjugates thereof are described. EntKL provides an attachment point for cargos such as fluorophores or antimicrobial payloads. Corresponding conjugates are recognized by outer membr...

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Autores principales: Zscherp, Robert, Coetzee, Janetta, Vornweg, Johannes, Grunenberg, Jörg, Herrmann, Jennifer, Müller, Rolf, Klahn, Philipp
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336463/
https://www.ncbi.nlm.nih.gov/pubmed/34377407
http://dx.doi.org/10.1039/d1sc02084f
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author Zscherp, Robert
Coetzee, Janetta
Vornweg, Johannes
Grunenberg, Jörg
Herrmann, Jennifer
Müller, Rolf
Klahn, Philipp
author_facet Zscherp, Robert
Coetzee, Janetta
Vornweg, Johannes
Grunenberg, Jörg
Herrmann, Jennifer
Müller, Rolf
Klahn, Philipp
author_sort Zscherp, Robert
collection PubMed
description The design, synthesis and biological evaluation of the artificial enterobactin analogue EntKL and several fluorophore-conjugates thereof are described. EntKL 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 (ΔG(sol)) and relaxed Fe–O force constants of the corresponding [Fe-EntKL]3− complexes indicated a similar iron binding constant compared to natural enterobactin (Ent). The synthesis of EntKL 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 EntKL 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 BODIPY(FL)-conjugates, demonstrated the ability of EntKL 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.
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spelling pubmed-83364632021-08-09 Biomimetic enterobactin analogue mediates iron-uptake and cargo transport into E. coli and P. aeruginosa Zscherp, Robert Coetzee, Janetta Vornweg, Johannes Grunenberg, Jörg Herrmann, Jennifer Müller, Rolf Klahn, Philipp Chem Sci Chemistry The design, synthesis and biological evaluation of the artificial enterobactin analogue EntKL and several fluorophore-conjugates thereof are described. EntKL 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 (ΔG(sol)) and relaxed Fe–O force constants of the corresponding [Fe-EntKL]3− complexes indicated a similar iron binding constant compared to natural enterobactin (Ent). The synthesis of EntKL 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 EntKL 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 BODIPY(FL)-conjugates, demonstrated the ability of EntKL 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. The Royal Society of Chemistry 2021-06-17 /pmc/articles/PMC8336463/ /pubmed/34377407 http://dx.doi.org/10.1039/d1sc02084f Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Zscherp, Robert
Coetzee, Janetta
Vornweg, Johannes
Grunenberg, Jörg
Herrmann, Jennifer
Müller, Rolf
Klahn, Philipp
Biomimetic enterobactin analogue mediates iron-uptake and cargo transport into E. coli and P. aeruginosa
title Biomimetic enterobactin analogue mediates iron-uptake and cargo transport into E. coli and P. aeruginosa
title_full Biomimetic enterobactin analogue mediates iron-uptake and cargo transport into E. coli and P. aeruginosa
title_fullStr Biomimetic enterobactin analogue mediates iron-uptake and cargo transport into E. coli and P. aeruginosa
title_full_unstemmed Biomimetic enterobactin analogue mediates iron-uptake and cargo transport into E. coli and P. aeruginosa
title_short Biomimetic enterobactin analogue mediates iron-uptake and cargo transport into E. coli and P. aeruginosa
title_sort biomimetic enterobactin analogue mediates iron-uptake and cargo transport into e. coli and p. aeruginosa
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336463/
https://www.ncbi.nlm.nih.gov/pubmed/34377407
http://dx.doi.org/10.1039/d1sc02084f
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