This study has been devoted to the synthesis and the evaluation of the therapeutic potential of a small library of L-iminosugars in cystic fibrosis. L-iminosugars belong to the most promising class of glycomimetics, molecules whose skeleton resembles that of natural carbohydrates and thanks to which they are able to have an effective interaction with numerous therapeutic targets (receptors, enzymes, proteins, etc.).

Our previous studies (FFC#22/2015, FFC#23/2018 e FFC#20/2019) revealed that the iminosugar L-Miglustat, under evaluation as anti-inflammatory agent in murine models of P. aeruginosa lung infection, exhibited an unexpected antibacterial activity. On this basis, in this project a small library of L-Miglustat analogues were synthesized to explore their antibacterial and antibiofilm properties by in vitro and in vivo studies. The compounds were evaluated against a panel of Gram (+) and (-), Candida species and against Non-Tuberculous Mycobacteria. In vitro studies enable us to identify two promising compounds whose antibacterial properties have been validated in murine models of P. aeruginosa acute and chronic lung infection, thanks to the collaboration with CFaCore service of FFC Ricerca. The innovative chemical structure of these compounds and the different molecular targets compared to those of conventional antibiotics could represent an additional weapon in the fight against antibiotic resistance. Completing the preclinical evaluation to establish the true antibacterial potential of these compounds may pave the way for new therapeutic perspectives in CF lung disease.