Abstract EN:

We have studied bacteriophages infecting Pseudomonas aeruginosa to develop antibacterial strategies. First, we aimed at understanding the molecular mechanisms underlying viral strategies to hijack bacterial functions. We studied the phage gene gp92, and found that its ectopic expression alters bacterial morphology, motility and provokes a major shift of the cell proteome, without affecting growth. Gp92 also impairs the AlgU membrane stress response, via its interaction with MucA. This disruption may help control phage lysis timing. Finally, expression of gp92 increased the susceptibility of P. aeruginosa to antibiotics, including Imipenem, thus revealing a new target for drug design.In a second project, we studied phage therapy efficacy and bacterial resistance in immunocompromised MyD88-/- mice. In these mice monophage therapy fails due to the uncontrolled growth of phage-resistant bacteria. To limit this growth, we evaluated two phages recognizing different bacterial receptors and their combination. In vitro, monophage treatments failed to limit phage-resistance growth while the combination succeeded. In contrast, the combination was not associated with higher efficacy than monophage treatments in MyD88-/- mice. Our results suggest that bacteria will not resist to every phage the same way and that in vitro experiments are not predictive of phage therapy success in vivo.