Pathogenic bacteria easily develop resistance to conventional antibiotics, moreover the formation of biofilm further increases resistance in chronic lung infections in cystic fibrosis. Antimicrobial peptides show antibacterial, antibiofilm and anti-inflammatory activities and very rarely give rise to resistant strains but

sensitivity to proteases limits their usefulness as drugs. A possible solution is to design antimicrobial peptidomimetics resistant to proteases like the so-called peptoids. However, peptides and peptoids are difficult to administer, due to their properties (i.e. high molecular weight and adhesiveness), which preclude an adequate biodistribution. Direct delivery to the lung could be an intriguing solution but it requires the use of inhalable formulations able to shield peptoid/lung barrier interaction and to allow good biodistribution and a controlled release kinetic. The aim of the project is to develop inhalable polymeric nanoparticles for lung delivery of P13#1, an antimicrobial peptoid previously designed by the proponents, alone and in combination with colistin or tobramycin, antibiotics widely used in the treatment of lung infection. Particular attention will be paid to nanoparticle features governing their interactions with infected lung barriers, such as sticky mucus and bacteria biofilm. The most promising formulations will be tested in vivo in a mouse model of lung chronic infection by P. aeruginosa.
The composition of the nanoparticles will improve the penetration inside biofilm and mucus thus further improving the antimicrobial action. The cooperation between the different antimicrobials will likely allow to further reduce onset of resistance and to reduce the dose of each single antimicrobial thus reducing toxicity. The inhalable formulations could help to control infection with a reduced number of administrations. Finally, the improvement of the nanoparticle production technology will facilitate the development of other therapies with direct delivery of drugs to the lung.