NAtriuretic Peptides drug optimization for dispersing Pseudomonas aeruginosa biOfilm and in vivo vaLidatiON – APPOLON

Cystic fibrosis (CF) patients often died from the consequences of recurrent chronic respiratory infections mostly due to Pseudomonas aeruginosa. These infections are not controlled due to frequent antibiotic-resistance, a tolerance to antimicrobials due to bacteria forming biofilms. Since new antimicrobial drugs are not emerging despite strong research, we urgently need complementary approaches improving the activity of antimicrobial drugs such as antibiofilm agents. We have recently identified the strong ability of natriuretic peptides (NPs) to disperse established biofilm and to facilitate the elimination of chronic infection by P. aeruginosa in mice model, after binding to a specific bacterial target. Interestingly, NPs potentiates the antibacterial activity of antibiotic and we have identified members of this family with different activity allowing to define a structure-activity relationship. The aim of APPOLON project is to generate the ideal drug candidate as a peptide derived from NPs for the treatment of recurrent infection by P. aeruginosa in CF patient. For this we will 1) Identify, in vitro among all available NPs, the most active peptide against established biofilms; 2) Modify the most active peptides to optimize their efficacy and their bioavailability; 3) Validate the effect of the two most active modified peptides in WT and in Scnn1b-Tg mice which mimics CF; 4- Detail the mechanism of action of peptides on bacterial biofilms and its impact on bacteria fitness. The results obtained in this project will allow to rapidly propose a drug candidate for the eradication of chronic respiratory infections. This soft approach will probably avoid the risk of setting up a resistance mechanism to this drug. This is essential for CF patients although this might have some applications for intubated patients in intensive care units and with acute exacerbations of chronic obstructive pulmonary disease (COPD).