Jury

  • Prof. Steve LANNERS (UNamur), Chair
  • Prof. Johan WOUTERS (UNamur), Secretary
  • Prof. Pierre FRANCOTTE (ULiège)
  • Dr. Marie HAUFROID (UCB)
  • Prof. Lionel POCHET (UNamur)

Abstract

Currently, Mycobacterium tuberculosis remains the second deadliest infectious agent in the world, responsible for 1.6 million deaths in 2021. The burden and cost of current treatment (6 months and 4,000 euros), coupled with the alarming emergence of antibiotic-resistant strains, underscore the absolute urgency of developing new therapeutic molecules. This study focuses on the Mycobacterium tuberculosis phosphoserine phosphatase (MtSerB2), an enzyme essential for serine biosynthesis and vital to the pathogen’s survival. Furthermore, this protein plays a key role in host invasion (through its interactions with the NF-κB factor and the cellular cytoskeleton), making MtSerB2 a prime therapeutic target for the development of new, potent anti-tuberculosis drugs.

One of the innovative strategies explored in this thesis is based on destabilizing the protein’s structure (disruption of protein structure). The goal is to design a molecule capable of disrupting the enzyme’s conformation, thereby causing it to lose its catalytic activity. This new class of molecules is expected to exhibit significantly higher selectivity for MtSerB2 compared to its human homolog, human phosphoserine phosphatase (hPSP).

To this end, the Mycobacterium avium phosphoserine phosphatase (MaSerB) was initially used as a model system, justified by its 83% sequence identity with MtSerB2 and its propensity to crystallize rapidly. Initially, a virtual screening of drugs already available on the market was conducted to identify potential inhibitors of MaSerB. Enzymatic assays based on malachite green detection

were then performed to evaluate the inhibitory activity of the various candidates. The results demonstrated increased selectivity of these compounds for dimeric proteins (MtSerB2 and MaSerB) compared to the human enzyme hPSP.

Notably, subsequent enzymatic assays conducted directly on MtSerB2 revealed response profiles that differed from those observed with the MaSerB model. To elucidate the molecular basis of these differences, the structure of the protein in its ligand-bound state is currently being investigated. To this end, protein-inhibitor complexes have been crystallized and will be analyzed by X-ray diffraction.