Study of the structure and inhibition of Mycobacterium avium phosphoserine phosphatase

Abstract

Tuberculosis remains currently one of the top ten causes of death worldwide. As a matter of fact, Mycobacterium tuberculosis (M.tb), which is the pathogen responsible for this disease, spreads easily and quickly through saliva droplets in air. Moreover, this bacterium is becoming more and more multidrug-resistant. Hence, new therapeutic targets need to be found in order to design new efficient drugs against M.tb.
Multiple previous experiments in our research group focus on M.tb phosphoserine phosphatase (SerB2) as new perfect therapeutic target, for three main reasons. Firstly, the enzyme is vital for the pathogen: SerB2 inhibition stops the biosynthetic pathway of L-serine and leads to bacterial death. In addition, SerB2 possesses an intrinsic pathogenic effect and expedites the infection. Finally, the primary sequence of phosphoserine phosphatase is highly conserved among pathogens. The study of its inhibition could therefore lead to the design of a drug, used as panacea, especially against tuberculosis.
As a result of our research, some efficient inhibitors have been discovered, thanks to the screening of NAMEDIC’s chemo-library. However, the precise mechanism of action of the aforementioned inhibitors remains unclear because the crystallographic structure of SerB2 was never obtained. The main goal of this research project is the study of the closest counterpart of SerB2 (83.7% of identity) that can be crystallized: the Mycobacterium avium phosphoserine phosphatase (SerB). Indeed, this enzyme can be overexpressed, and crystallized after an optimized purification. Our results show that SerB2 inhibitors follow similar enzymatic kinetics and remain effective against SerB. In addition, some crystallographic assays of SerB complexed with the inhibitors and some amino acids have led to new experimental structures of SerB complexed with selected ligands. Interactions between the enzyme and these compounds are studied to provide more information about the structure and the inhibition of SerB2.

Date of Award	24 Jan 2019
Original language	English
Awarding Institution	University of Namur
Supervisor	Johan Wouters (Supervisor)