The aim is to define whether, how and to what extent CFTR-modulators have an antibacterial effect – alone or in combination with standard treatments – and/or impact on host response/defense during long-term chronic pneumonia. A bio-bank of common pathogenic isolates recovered from CF patients will be tested in vitro for susceptibility to CFTR-modulators alone or in combination with antibiotics commonly used in the CF clinics. Next, CFTR-modulators will be administered intraperitoneally and tested in mouse models of chronic lung infection to study their anti-bacterial activity and the potential effects of CFTR-modulators on the host defense. Alone or in combination with antibiotics, the impact of CFTR-modulators in these models will be evaluated on the general health status, the lung function, the incidence and the severity of chronic infection, innate and adaptive immune responses and inflammatory markers, and tissue damage. This proposal could provide a pre-clinical platform of infection models to test the off-target effects of CFTR-modulators and generate recommendations for their use alone and in combination with antibiotic treatments.