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Reference : UMR6296-SOPROY-002
Workplace : AUBIERE
Date of publication : Monday, May 03, 2021
Scientific Responsible name : Sophie FAURE (ROY)
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 September 2021
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
Critical challenges remain in the battle against infectious diseases. The emergence of antimicrobial resistances is not the unique serious threat for patients. Infections associated with bacterial specific lifestyles such as sanctuarization in biofilm or inside cells, are also difficult-to-treat with currently available antibiotics. Therefore, there is not only a need to develop novel antibacterial agents but also to characterize molecules able to target bacteria embedded in biofilms and those with intracellular growth. In this context, natural antimicrobial peptides (AMPs) are a great source of inspiration for the development of safe and efficient new generations of antimicrobial agents. Notably, many peptidomimetics have been designed to exhibit the cationic amphipathic helical secondary structure of native AMPs, which is the key determinant of their activity by interaction with bacterial membranes. Previous studies suggest that the shape of the amphipathic oligomer can dramatically influence the mode of interaction with membranes and therefore the mechanism of action.
Peptoid-type oligoamides is a particular class of foldamers that, due to their intrinsic properties, do not adopt secondary structure induced by a network of intramolecular hydrogen bonds. The chemists, notably the PEPTOID group from ICCF, have made the conformational flexibility of the peptoid backbone an asset by developing conformational control tools that allow the personalized design of various secondary structures. The doctoral work will focus on the design, synthesis and study of new peptoid-type amphiphilic architectures with varied secondary structures (helix, ribbon …etc). For the design of these architectures, the project is based on i) the intrinsic properties of different peptoid-type skeletons, ii) new structuring tools and iii) promising results concerning the antibacterial activities of short peptoid oligomers based on triazolium. For the preparation of the various edifices, synthesis methods in solution or on support will be used to access linear or cyclic oligomers. The conformational preferences of these oligomers will be studied by 1D and 2D NMR, X-ray diffraction, circular dichroism and molecular modeling. The capacity of the various amphiphilic oligomers to eradicate Gram + and/or Gram- bacteria in biofilm or intracellular form will be evaluated and their mechanism of action studied by our microbiologist and biophysicist partners.
References:  Zuckermann R., Kodadek T. Curr.Opin. Mol. Ther. 2009, 11, 299.  Roy O., Dumonteil G., Faure S., Jouffret L., Kriznik A., Taillefumier C. J. Am. Chem. Soc. 2017, 139, 13533 and references herein.  Shyam R., Charbonnel N., Job A., Blavignac C., Forestier C., Taillefumier C., Faure S. ChemMedChem 2018, 15, 1513.
The PhD work will be performed at the Chemistry Institute of Clermont-Ferrand (ICCF UMR CNRS 6296) in the PEPTOID group from the team Organic and Medicinal Chemistry (COM). ICCF is a multidisciplinary institute in Chemistry bringing together 120 permanent staff in which the COM team develops projects at the Chemistry-Biology interface.
This PhD project is part of the ANR project AmphiPep «Engineering antibacterial cationic amphipathic peptidomimetics for targeting biofilm-embedded and intracellular bacteria » including four partners: 1) Institut de Chimie de Clermont-Ferrand (ICCF), UMR CNRS 6296 – UCA ; 2) Laboratoire Microorganismes : Génome Environnement (LMGE) UMR CNRS 6023 – UCA ; 3) Centre International de Recherche en Infectiologie (CIRI), INSERM U1111-CNRS UMR5308-ENS Lyon-UCBL1 et 4) Institut de Chimie de Strasbourg (IC) CNRS UMR 7177.
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