Beta-sitosterol (BSS) is commercially available whereas L-miglustat was synthesized and purified (Department of Chemical Sciences, University of Napoli Federico II- Napoli, Italy). BSS and L-miglustat were evaluated in wild type mice infected with Pseudomonas aeruginosa (Pa) and treated by gavage. BSS induced a dose-dependent reduction of bacteria recovered in broncholavage (BAL) and lungs of acute and chronic infected mice, moreover a decrease of neutrophils and increase of alveolar macrophages recruited in BAL and an overall improvement of health parameters. Surprisingly, L-miglustat showed anti-infective activity in chronically infected mice, reduced neutrophils and increased bacterial clearance. The extension project FFC#20/2019 will further study both the compounds in vitro on abiotic surfaces and airway epithelial cells under experimental conditions simulating CF lung environment. Results from the whole pre-clinical investigation could provide a proof of concept for planning clinical trials. BSS has been already tested in clinical trials as an adjuvant to statins in dyslipidemia. It could be repositioned as an anti-inflammatory drug for CF lung disease. L-miglustat could obtain an orphan drug designation as an anti-inflammatory/anti-infective agent against chronic Pa infections.