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© Bruno Dupuy, Claire Morvan, Institut Pasteur
Cellules végétative et spores de Clostridioides difficile / Vegative cells and spores of Clostridioides difficile
Publication : Molecular microbiology

Role of the global regulator Rex in control of NAD -regeneration in Clostridioides (Clostridium) difficile

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Molecular microbiology - 18 Mar 2019

Bouillaut L, Dubois T, Francis MB, Daou N, Monot M, Sorg JA, Sonenshein AL, Dupuy B

Link to Pubmed [PMID] – 30882947

Mol. Microbiol. 2019 Mar;

For the human pathogen Clostridioides (also known as Clostridium) difficile, the ability to adapt to nutrient availability is critical for its proliferation and production of toxins during infection. Synthesis of the toxins is regulated by the availability of certain carbon sources, fermentation products and amino acids (e.g. proline, cysteine, isoleucine, leucine and valine). The effect of proline is attributable at least in part to its role as an inducer and substrate of D-proline reductase (PR), a Stickland reaction that regenerates NAD from NADH. Many Clostridium spp. use Stickland metabolism (co-fermentation of pairs of amino acids) to generate ATP and NAD . Synthesis of PR is activated by PrdR, a proline-responsive regulatory protein. Here we report that PrdR, in the presence of proline, represses other NAD -generating pathways, such as the glycine reductase and succinate-acetyl CoA utilization pathways leading to butyrate production, but does so indirectly by affecting the activity of Rex, a global redox-sensing regulator that responds to the NAD /NADH ratio. Our results indicate that PR activity is the favored mechanism for NAD regeneration and that both Rex and PrdR influence toxin production. Using the hamster model of C. difficile infection, we revealed the importance of PrdR-regulated Stickland metabolism in the virulence of C. difficile.