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Intracellular multiplication and dissemination of the infectious bacterial pathogen F rancisella tularensis implies the utilization of multiple host-derived nutrients. Here, we demonstrate that gluconeogenesis constitutes an essential metabolic pathway in F rancisella pathogenesis. Indeed, inactivation of gene glp X, encoding the unique fructose 1,6-bisphosphatase of F rancisella, severely impaired bacterial intracellular multiplication when cells were supplemented by gluconeogenic substrates such as glycerol or pyruvate. The Δ glp X mutant also showed a severe virulence defect in the mouse model, confirming the importance of this pathway during the in vivo life cycle of the pathogen. Isotopic profiling revealed the major role of the Embden- Meyerhof (glycolysis) pathway in glucose catabolism in F rancisella and confirmed the importance of glp X in gluconeogenesis. Altogether, the data presented suggest that gluconeogenesis allows F rancisella to cope with the limiting glucose availability it encounters during its infectious cycle by relying on host amino acids. Hence, targeting the gluconeogenic pathway might constitute an interesting therapeutic approach against this pathogen. [ABSTRACT FROM AUTHOR]