Vincent Nivière

​​The ability of microorganisms to resist various forms of stress is crucial for their survival and is a key factor in the virulence of pathogens. Understanding the mechanisms behind this resistance is of first interest for developing new types of antibiotics that specifically target these defense systems. In this context, we are investigating the MsrPQ enzymatic system, which enables bacteria to withstand HOCl-induced stress.

Hypochlorous acid (HOCl, commonly known as bleach) is a powerful oxidant highly toxic to microorganisms. Its production by the innate immune system is used as a first line of defense against pathogens. HOCl primarily targets methionine residues in proteins, oxidizing them into methionine sulfoxide (Met-SO). This oxidation causes major alterations in protein structure, leading to the loss of their function, ultimately resulting in pathogen death.

​Recent discoveries have shown that some bacteria express a novel type of methionine sulfoxide reductase (Msr), allowing them to resist HOCl stress by repairing oxidized methionines. This MsrPQ system is characterized by: i) The presence of a molybdenum cofactor in the active site of MsrP, whereas previously characterized Msr enzymes did not involve metal atoms in catalysis. ii) Periplasmic localization. iii) Specific association of MsrP with the membrane-bound cytochrome MsrQ, both proteins being encoded in a same operon.

Interestingly, some intracellular pathogenic bacteria have a duplication of the MsrPQ operon in their genomes, located in DNA sequences associated with pathogenicity islands. This suggest an important role for MsrPQ in the virulence of these pathogens.

Our project aims to provide a detailed understanding of the enzymatic mechanism of MsrPQ, from both molecular and structural perspectives. Specifically, we seek to characterize the electron transfer processes associated with the various redox cofactors, Mo, heme, flavin, and quinone, present in MsrPQ.