Reference : UMR9004-MICBLA-001
Workplace : MONTPELLIER
Date of publication : Tuesday, May 3, 2022
Scientific Responsible name : Mickael Blaise
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 3 October 2022
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
According to the World Health Organization each year, approximately 1.5 million people die of tuberculosis (TB) and 10 million people are newly infected. Despite the existence of effective treatments, the TB mortality remains very high due to co-infection with HIV, the difficulty in diagnosing the disease, and the emergence of multi-, ultra- or totally- resistant strains of Mycobacterium tuberculosis to antibiotics.
Thus, it is urgent, to stop the progression of the disease, counteract drug resistance, develop new therapeutic strategies, and in particular find new pharmacological targets. The mycobacterial cell wall (mycomembrane) is very atypical and differs from the one of the classical gram-positive bacteria. The presence of fatty acids notably mycolic acids with very long aliphatic chains renders the cell wall very hydrophobic and thus limits drug penetration. The enzymes involved in the synthesis of the mycomembrane are often essential for the growth of the bacillus and represent potential therapeutic
The trehalose monomycolate (TMM) transporter called MmpL3 flips TMM over the plasma membrane. Thus, MmpL3 is essential for the mycomembrane constitution and has emerged in recent years as a very interesting therapeutic target to exploit. Although the three-dimensional structure of MmpL3 has been solved, the molecular details of TMM transport, as well as the mode of action of inhibitors targeting MmpL3, remain to be fully understood.
The thesis project will focus on the structural and functional study of MmpL3. This project will involve various techniques including molecular biology, biochemistry (production and purification of recombinant membrane and soluble proteins), structural biology (X-ray crystallography and cryo-electron microscopy), and bioinformatics.
The thesis must begin on October 1st, 2022, and will be fully funded for 36 months by the CNRS as part of the joint CNRS-University of Copenhagen program. The student will work at IRIM in the “Bacterial Enzymes and antibiotic resistance” team.
The project will involve a close collaboration with the group of Dr. Pontus Gourdon at the University of Copenhagen, Denmark. In particular, the PhD thesis student will have to spend a total of 6 months over several stays in the Danish laboratory.
The PhD thesis will be funded by the joint program CNRS-Copenhagen University. The PhD student will work mainly in the BEAR team at the ''Institut de Recherche en Infectiologie de Montpellier''
Constraints and risks
The PhD student will spend a mininum of 6 months (over several stays) at the danish institute.
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