Histidinylated polylysines: An alternative antibacterial and fluidifying agent in cystic fibrosis.**

Introduction: We recently showed that polycationic polymers such as poly-L-Lysines (pLK) were able to compact DNA, liquefy sputum of cystic fibrosis (CF) patients, inhibit bacterial growth (Pseudomonas aeruginosa and Staphylococcus aureus) , and favor the control of neutrophil proteases by exogenous protease inhibitors (Dubois et al. , AJRCCM, 2013). Thus, pLK represent a promising alternative to the combination of alpha-dornase and antibiotics that remains the main therapeutics to tentatively control the progression of CF. pLKs however display some cytotoxicity depending on their length and their charge density. Aim: The aim of this study was to develop an optimized polycationic compound with low cytotoxicity but with similar properties to those of original pLKs. Methods: We synthesized polylysyl skeletons of different length that were grafted with an increasing number of histidyl or gluconoyl residues to impact on their charge at neutral pH. All compounds were assayed for their cellular cytotoxicity, their ability to compact DNA, their antimicrobial activity and their anti-inflammatory potential. The best candidate was then assessed in Balb/c mice for its in vivo tolerance and anti- P. aeruginosa activity. Results: We found that pLK30-His8* showed a far less cytotoxicity than original pLKs while it retained similar properties on DNA, bacteria and proteases present in CF sputum. pLK30-His8* at 10 mg/kg was well-tolerated upon instillation in the lungs of mice and significantly reduced the bacteria load in P. aeruginosa -infected mice. Conclusion: pLK30-His8 is a promising anti-inflammatory agent in CF. *Patent PCT/EP2013/060799 **This work was supported by french CF Foundation (VLM).