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PhD position at the chemistry/biochemistry interface (M/W): New selective inhibitors for deciphering lipid metabolism and virulence in M. tuberculosis

This offer is available in the following languages:
Français - Anglais

Date Limite Candidature : vendredi 6 novembre 2020

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General information

Reference : UMR7255-JEACAV-002
Workplace : MARSEILLE,MARSEILLE 09
Date of publication : Friday, October 16, 2020
Scientific Responsible name : JF Cavalier
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 December 2020
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly

Description of the thesis topic

Tuberculosis, which affects one third of the world's population and is still responsible for nearly 1.5 million deaths per year, remains a major public health problem. Therefore, it is important to study the physiology of Mycobacterium tuberculosis (M. tb), the agent responsible for this disease, in order to develop new and effective tools to combat its spreading. During the infection, M. tb is able to induce the differentiation of certain macrophages into foamy macrophages (FM) which are cells loaded with Lipid Bodies (LB). M. tb is then able to use these host lipids for its own: renewal of the lipids of the envelope, formation of lipid reserves for its entry into dormancy and their consumption upon reactivation. These different stages imply the existence of extra- and intracellular lipolytic enzymes, but above all this suggests that the use of these lipids is one of the characteristics of the life cycle of M. tb.
It is indeed recognized that mycobacterial lipolytic enzymes are involved in the host-pathogen cross-talk and play a major role in the physio-pathology of the disease during the active and persistent phases of infection, making these enzymes attractive therapeutic targets. Therefore, finding ways to block the action of these lipolytic enzymes would pave the way for the discovery of new treatments against tuberculosis.
We have recently synthesized series of Cyclipostins/Cyclophostins (CyC) analogues [1-4] and Oxadiazolone (OX) [4-7] derivatives that are non-toxic to host cells, and which target various mycobacterial enzymes involved in lipid metabolism with very promising antituberculosis activities.

This thesis project is part of the ANR LipInTB project (2019-2024), involving 5 partners, which aims to use these two families of inhibitors as probes to decipher the lipid metabolism of M. tb during its growth and virulence.

The main objectives of this ambitious project at the interface between chemistry, biochemistry, biology and antibiotic therapy are: 1) to study the penetration and distribution of our inhibitors in the bacterium as well as in host cells; 2) to use our inhibitors as probes to study the lipid metabolism in M. tb by identifying the enzymes impacted by our compounds during the active replication, latency and reactivation phases in infected macrophages; 3) to biochemically and structurally characterize the identified target enzymes, 4) to validate them in vitro and ex vivo by building deletion / complementation / overexpressing mutant strains and studying their susceptibility and viability in infected macrophages; and 5) to chemical optimize the best probe compounds.

References: [1] Nguyen P.C., et al., Scientific Reports 2017, 7, 11751. [2] Nguyen P.C., et al., Int J Antimicrob Agents 2018, 51, 651-654. [3] Point V., et al., J Med Chem. 2012, 55, 10204-10219. [4] Cavalier, J.-F., et al., Eur J Med Chem 2020, https://doi.org/10.1016/j.ejmech.2020.112908. [5] Delorme V., et al., PLoS ONE 2012, 7, e46493. [6] Nguyen P.C., et al., Bioorg Chem. 2018, 81, 414-424. [7] Madani, A., et al., PLoS One 2020, 15, e0238178.

Work Context

The research work will be carried out at the Laboratoire d'Ingénierie des Systèmes Macromoléculaires (LISM) in the "Lipolysis and Bacterial Pathogenicity" (LBP) team (https://tuberculosis-lbp.wixsite.com/tuberculosis-lbpteam).

Our team specializes in the study of lipolytic enzymes in mycobacteria, is expert in medicinal chemistry in the design and biochemical study of inhibitors; in the production, purification and characterization of recombinant proteins; in lipid analysis (quantitative TLC) and electron and confocal microscopy (for the visualization of bacteria).

The student will have access to numerous techniques and will be able to interact with the 4 other partners of this multidisciplinary project, which will allow him/her to improve his/her knowledge to different fields, such as chemistry/biochemistry (in particular with the optimization of the click chemistry reaction), fluorescence imaging, microbiology, biomolecular biology, proteomics and crystallography.

Keywords: drug susceptibility; intracellular activity; activity based-protein profiling; mycobacteria; Tuberculosis, lipolytic enzyme, biochemistry

Constraints and risks

None

Additional Information

The student must have a master 2 level or equivalent (i.e., engineering school) with honors; and with a solid background in therapeutic chemistry, biochemistry, microbiology and/or biological chemistry (chemistry-biology interface). Experiences in biochemistry and/or molecular biology would be an asset.
Regarding this multidisciplinary project, knowledge or affinity for these different fields of expertise will be a plus. The candidate must also be motivated to train in various area complementary to his or her initial training, be organized, dynamic and communicative, and open-minded.

This thesis financed by the ANR on the LipInTB project is planned to start in December 2020.

The selected candidate will depend on the Doctoral School of Chemical Sciences (ED250) from Aix-Marseille University.

Please note that no application by email will be considered.
All applications must be submitted exclusively via the CNRS job portal and must include a detailed CV with the contact details of at least two referees (teachers or internship supervisors), a motivation letter, and transcripts of Master 1 and 2 as well as corresponding rankings.

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