From Peptide Aptamers to Inhibitors of FUR, Bacterial Transcriptional Regulator of Iron Homeostasis and Virulence

FUR (Ferric Uptake Regulator) protein is a global transcriptional regulator that senses iron status and controls the expression of genes involved in iron homeostasis, virulence, and oxidative stress. Ubiquitous in Gram-negative bacteria and absent in eukaryotes, FUR is an attractive antivirulence ta...

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Published in:ACS chemical biology 2016-09, Vol.11 (9), p.2519-2528
Main Authors: Mathieu, Sophie, Cissé, Cheickna, Vitale, Sylvia, Ahmadova, Aynur, Degardin, Mélissa, Pérard, Julien, Colas, Pierre, Miras, Roger, Boturyn, Didier, Covès, Jacques, Crouzy, Serge, Michaud-Soret, Isabelle
Format: Article
Language:English
Subjects:
Aptamers, Peptide - pharmacology
Bacterial Proteins - antagonists & inhibitors
Bacteriology
Biochemistry, Molecular Biology
Escherichia coli - metabolism
Escherichia coli - pathogenicity
Genomics
Homeostasis
Human health and pathology
Iron - metabolism
Life Sciences
Microbiology and Parasitology
Molecular Docking Simulation
Repressor Proteins - antagonists & inhibitors
Two-Hybrid System Techniques
Virulence
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cited_by cdi_FETCH-LOGICAL-a376t-a0b93243f91d98011023e1cce063eef422ba3c6652f94ec013b58abad72437db3
cites cdi_FETCH-LOGICAL-a376t-a0b93243f91d98011023e1cce063eef422ba3c6652f94ec013b58abad72437db3
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creator Mathieu, Sophie
Cissé, Cheickna
Vitale, Sylvia
Ahmadova, Aynur
Degardin, Mélissa
Pérard, Julien
Colas, Pierre
Miras, Roger
Boturyn, Didier
Covès, Jacques
Crouzy, Serge
Michaud-Soret, Isabelle
description FUR (Ferric Uptake Regulator) protein is a global transcriptional regulator that senses iron status and controls the expression of genes involved in iron homeostasis, virulence, and oxidative stress. Ubiquitous in Gram-negative bacteria and absent in eukaryotes, FUR is an attractive antivirulence target since the inactivation of the fur gene in various pathogens attenuates their virulence. The characterization of 13-aa-long anti-FUR linear peptides derived from the variable part of the anti-FUR peptide aptamers, that were previously shown to decrease pathogenic E. coli strain virulence in a fly infection model, is described herein. Modeling, docking, and experimental approaches in vitro (activity and interaction assays, mutations) and in cells (yeast two-hybrid assays) were combined to characterize the interactions of the peptides with FUR, and to understand their mechanism of inhibition. As a result, reliable structure models of two peptide–FUR complexes are given. Inhibition sites are mapped in the groove between the two FUR subunits where DNA should also bind. Another peptide behaves differently and interferes with the dimerization itself. These results define these novel small peptide inhibitors as lead compounds for inhibition of the FUR transcription factor.
doi_str_mv 10.1021/acschembio.6b00360
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source American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list)
subjects Aptamers, Peptide - pharmacology
Bacterial Proteins - antagonists & inhibitors
Bacteriology
Biochemistry, Molecular Biology
Escherichia coli - metabolism
Escherichia coli - pathogenicity
Genomics
Homeostasis
Human health and pathology
Iron - metabolism
Life Sciences
Microbiology and Parasitology
Molecular Docking Simulation
Repressor Proteins - antagonists & inhibitors
Two-Hybrid System Techniques
Virulence
title From Peptide Aptamers to Inhibitors of FUR, Bacterial Transcriptional Regulator of Iron Homeostasis and Virulence
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