The Pentose Phosphate Pathway constitutes a major metabolic hub in pathogenicFrancisella

AbstractMetabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and hence represent potential targets for anti-bacterial strategies. Here, we addressed the role of the pentose phosphate pathway (PPP) and its connections with other metabolic pathways in the pathophysiology ofFrancisella novicida. The involvement of the PPP inFrancisellaintracellular life cycle was first demonstrated with the study of PPP inactivation mutants. Indeed, inactivation oftktA, rpiAorrpegenes, severely impaired intramacrophagic multiplication during the first 24 hours. Time-lapse video microscopy demonstrated thatrpiAandrpemutants were able to resume late intracellular bacterial multiplication. To get further insight into the links between the PPP and other metabolic networks of the bacterium, we next performed a thorough proteo-metabolomic analysis of these mutants. We show that the PPP constitutes a major bacterial metabolic hub with multiple connections with glycolysis, tricarboxylic acid cycle and other pathways, such as fatty acid degradation and sulfur metabolism. Hence, our study highlights how the PPP is instrumental toFrancisellapathogenesis and growth in its intracellular niche.