Enterobactin- and salmochelin-β-lactam conjugates induce cell morphologies consistent with inhibition of penicillin-binding proteins in uropathogenic Escherichia coli CFT073
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d0sc04337k.pdf
Description
Published version
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1.47 MB
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Checksum (MD5)
63795655288c8ca71bd7825f9b606431
Author(s)
Sargun, Artur
Johnstone, Timothy C
Zhi, Hui
Raffatellu, Manuela
Nolan, Elizabeth M
Date Issued
2021
Journal
Chemical Science
Publisher
Royal Society of Chemistry (RSC)
Citation
Sargun, Artur, Johnstone, Timothy C, Zhi, Hui, Raffatellu, Manuela and Nolan, Elizabeth M. 2021. "Enterobactin- and salmochelin-β-lactam conjugates induce cell morphologies consistent with inhibition of penicillin-binding proteins in uropathogenic Escherichia coli CFT073." Chemical Science, 12 (11).
Version
Final published version
Abstract
The design and synthesis of narrow-spectrum antibiotics that target a specific bacterial strain, species, or group of species is a promising strategy for treating bacterial infections when the causative agent is known. In this work, we report the synthesis and evaluation of four new siderophore-β-lactam conjugates where the broad-spectrum β-lactam antibiotics cephalexin (Lex) and meropenem (Mem) are covalently attached to either enterobactin (Ent) or diglucosylated Ent (DGE) via a stable polyethylene glycol (PEG3) linker. These siderophore-β-lactam conjugates showed enhanced minimum inhibitory concentrations against Escherichia coli compared to the parent antibiotics. Uptake studies with uropathogenic E. coli CFT073 demonstrated that the DGE-β-lactams target the pathogen-associated catecholate siderophore receptor IroN. A comparative analysis of siderophore-β-lactams harboring ampicillin (Amp), Lex and Mem indicated that the DGE-Mem conjugate is advantageous because it targets IroN and exhibits low minimum inhibitory concentrations, fast time-kill kinetics, and enhanced stability to serine β-lactamases. Phase-contrast and fluorescence imaging of E. coli treated with the siderophore-β-lactam conjugates revealed cellular morphologies consistent with the inhibition of penicillin-binding proteins PBP3 (Ent/DGE-Amp/Lex) and PBP2 (Ent/DGE-Mem). Overall, this work illuminates the uptake and cell-killing activity of Ent- and DGE-β-lactam conjugates against E. coli and supports that native siderophore scaffolds provide the opportunity for narrowing the activity spectrum of antibiotics in clinical use and targeting pathogenicity.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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Creative Commons Attribution NonCommercial License 3.0
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DOI of Published Version
https://doi.org/10.1039/D0SC04337K
