Skip to Main content Skip to Navigation
Theses

Structural studies on inhibition mechanisms, oligomerization and DNA binding of the transcription regulator Fur : from in silico simulations to in vitro biological assays

Abstract : The most commonly prescribed drugs in human medicine are antibiotics. Since their discovery, they have drastically impacted the way we treat infections. However, a bacterium eventually becomes resistant to antimicrobial treatment through the natural process of adaptative evolution. Even if resistant bacteria are omnipresent in the biosphere, their emergence rate is accelerated by the misuse of antimicrobial agents leading to the public health threat we are facing now. As currently available antimicrobial agents lose their effectiveness and very few new drugs are being developed, a breakthrough in new strategies to fight pathogens should be a priority. Ideal new therapeutic targets should exert weak evolutionary pressure, disarm or weaken the pathogen and be unique to microorganisms. One way to do so is by interfering with the iron regulation and its homeostasis within Bacteria. The bioavailability of iron strongly influenced early life and the metabolic strategies that sustained it. A central iron sensing mechanism evolved to ensure the regulation of such an important element. Sadly for bacteria this sensor became an exploitable weakness in our battle against infection. The “Ferric Uptake Regulator” is a metal dependent transcription regulator with a large regulatory network controlling iron homeostasis and bacterial virulence. This work continues previous investigations on Fur inhibitors using a combined experimental and theoretical approach by performing XAS, SAXS and MALLS experiments together with computer simulations. We describe for the first time the structures of Fur from E. coli in addition to a tetrameric Fur structure of a mutant from P. aeruginosa. Moreover, free energy profiles of Fur proteins, as tetramers or dimers bound to DNA, from different species were generated and key residues involved in the interactions determined, providing mechanistic insights into Fur complexes. The structural information gathered from this work will be used to better understand inhibition mechanisms of Fur proteins providing new opportunities to overcome drug development challenges.
Complete list of metadatas

Cited literature [324 references]  Display  Hide  Download

https://tel.archives-ouvertes.fr/tel-02050234
Contributor : Abes Star :  Contact
Submitted on : Wednesday, February 27, 2019 - 9:04:08 AM
Last modification on : Friday, November 6, 2020 - 4:27:33 AM
Long-term archiving on: : Tuesday, May 28, 2019 - 12:54:11 PM

File

NADER_2018_archivage.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-02050234, version 1

Collections

Citation

Serge Nader. Structural studies on inhibition mechanisms, oligomerization and DNA binding of the transcription regulator Fur : from in silico simulations to in vitro biological assays. Quantitative Methods [q-bio.QM]. Université Grenoble Alpes, 2018. English. ⟨NNT : 2018GREAV037⟩. ⟨tel-02050234⟩

Share

Metrics

Record views

208

Files downloads

1333