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Vectorization of peptides inhibitors of FUR as an antivirulence strategy targeting iron homeostasis

Published on 25 September 2024

Isabelle Michaud-Soret


The growing resistance of pathogenic bacteria to antibiotics is one of the major health challenges requiring the development of innovative molecules acting on new targets.
The Ferric uptake transcription regulators (Fur) are transcription factors that controls the expression of genes involved in iron homeostasis, oxidative stress and virulence. We studied Fur properties from several pathogens such as H. pylori, F. tularensis, P. aeruginosa and Escherichia coli [1-5]. We developed and characterize anti-Fur peptide inhibitors [6, 7, 8] as anti-virulence drugs. To be active in vivo, the inhibitors need to cross the bacterial envelope to reach the cytoplasm. In this context, the vectorization to siderophores analogs should make it possible. This type of peptide-siderophore, such as microcin E492, naturally produced, penetrates the bacteria via the natural pathways of the iron-enterobactin complex.
The goal of this project is to synthesize and test peptido-siderophores derived from anti-Fur peptides inhibitors already obtained for their ability to reduce virulence in order to obtain ultimately molecules with pharmacological applications. This work will be done in collaboration with G. Mislin (ENSB, Strasbourg) and E. Nolan (MIT, USA).


Model of 2 anti-Fur peptide inhibitors (in pink and purple interacting wit EcFur dimer (subunits in yellow and green)

Former Postdoc: Sophie Mathieu, Aynur Ahmadova, Mélissa Degardin
Financial support: LabEx ARCANE



[1] Pecqueur, L.; D'Autreaux, B.; Dupuy, J.; Nicolet, Y.; Jacquamet, L.; Brutscher, B.; Michaud-Soret, I.; Bersch, B., Structural changes of Escherichia coli ferric uptake regulator during metal-dependent dimerization and activation explored by NMR and X-ray crystallography. The Journal of biological chemistry 2006, 281 (30), 21286-21295. https://www.sciencedirect.com/science/article/pii/S0021925818952567?via%3Dihub

[2] Dian, C.; Vitale, S.; Leonard, G. A.; Bahlawane, C.; Fauquant, C.; Leduc, D.; Muller, C.; de Reuse, H.; Michaud-Soret, I.; Terradot, L., The structure of the Helicobacter pylori ferric uptake regulator Fur reveals three functional metal binding sites. Molecular microbiology 2011, 79 (5), 1260-75. https://doi.org/10.1111/j.1365-2958.2010.07517.x

[3] Perard, J.; Coves, J.; Castellan, M.; Solard, C.; Savard, M.; Miras, R.; Galop, S.; Signor, L.; Crouzy, S.; Michaud-Soret, I.; de Rosny, E., Quaternary Structure of Fur Proteins, a New Subfamily of Tetrameric Proteins. Biochemistry 2016, 55 (10), 1503-15. https://pubs.acs.org/doi/epdf/10.1021/acs.biochem.5b01061

[4] Perard, J.; Nader, S.; Levert, M.; Arnaud, L.; Carpentier, P.; Siebert, C.; Blanquet, F.; Cavazza, C.; Renesto, P.; Schneider, D.; Maurin, M.; Coves, J.; Crouzy, S.; Michaud-Soret, I., Structural and functional studies of the metalloregulator Fur identify a promoter-binding mechanism and its role in Francisella tularensis virulence. Communications biology 2018, 1, 93. https://www.nature.com/articles/s42003-018-0095-6.pdf

[5] Nader, S.; Perard, J.; Carpentier, P.; Arnaud, L.; Crouzy, S.; Michaud-Soret, I., New insights into the tetrameric family of the Fur metalloregulators. Biometals 2019, 32 (3), 501-519. https://hal.science/hal-02166207/file/Nader%20et%20al%20%20HAL%20Biometals2019.pdf

[6] Abed, N.; Bickle, M.; Mari, B.; Schapira, M.; Sanjuan-España, R.; Robbe Sermesant, K.; Moncorgé, O.; Mouradian-Garcia, S.; Barbry, P.; Rudkin, B., B.; Fauvarque, M.-O.; Michaud-Soret, I.; Colas, P., A comparative analysis of perturbations caused by a gene knock-out, a dominant negative allele, and a set of peptide aptamers. Molecular and Cellular Proteomics 2007, 6 (12), 2110-21. https://hal.science/hal-02975696/file/Michaud-Soret_Abed_2007.pdf

[7] Cissé, C.; Mathieu, S. V.; Ould Abeih, M. B.; Flanagan, L.; Vitale, S.; Catty, P.; Boturyn, D.; Michaud-Soret, I.; Crouzy, S., Inhibition of the Ferric Uptake Regulator by Peptides Derived from Anti-FUR Peptide Aptamers: Coupled Theoretical and Experimental Approaches. ACS chemical biology 2014, 9 (12), 2779-2786. https://pubs.acs.org/doi/10.1021/cb5005977

[8] Mathieu, S.; Cisse, C., Cissé; Vitale, S.; Ahmadova, A.; Degardin, M.; Perard, J.; Colas, P.; Miras, R.; Boturyn, D.; Covès, J.; Crouzy, S.; Michaud-Soret, I., From Peptide Aptamers to Inhibitors of FUR, Bacterial Transcriptional Regulator of Iron Homeostasis and Virulence. ACS chemical biology 2016, 11 (9), 2519-2528. https://pubs.acs.org/doi/epdf/10.1021/acschembio.6b00360 ​