Ricerc@Sapienza

Antimicrobial resistance represents an increasing threat to public health and makes urgent the need for new-generation antimicrobials with novel modes of action and potent therapeutic activity. Endogenous antimicrobial peptides (AMPs) adopt a facial amphiphilic structure when in contact with bacterial membranes, by winding into alpha-helical or ß-sheet structures with positive charges and lipophilic groups arranged on opposite sides. This facial amphiphilicity allows AMPs to efficiently bind to the negatively charged bacterial membranes and penetrate into them leading to cell death. In the fight against antimicrobial resistance, the development of new antimicrobials able to reproduce the main structural feature of AMPs, like peptide amphiphiles (PAs), is a major strategy. Unfortunately, PAs prepared by joining hydrophobic chains of conventional head-tail surfactants to hydrophilic cationic peptides, cannot fulfill the facial amphiphilicity of AMPs. Facial amphiphilicity is typical of bile acids (BAs), cholesterol-derived steroid acids that are produced in mammals and other vertebrates. This project is aimed at creating unconventional PAs by joining the facial amphiphilic skeletons of BAs to peptides, thereby adding a facial amphiphilic structure to PAs. Lysine-based peptides are used in order to provide a positive charge to the PAs. Conjugation at different sites of the BA molecules, such as the terminal carboxylic group or the hydroxyl bearing carbons, is investigated. Incorporation of D-amino acids is also considered in order to obtain protease resistant BA-based PAs. Beside the synthesis, the project focuses on the self-assembly of the PAs, which is known to regulate their local concentration and activity at the bacterial membrane. The loading of carriers is also investigated, which is generally used to efficiently and safely deliver antibiotics to infections, thereby overcoming problems hindering the antimicrobial efficacy such as proteolysis or toxicity