Ricerc@Sapienza

My research interest is mainly focused on the structure-function characterization of amphibian skin-derived antimicrobial peptides (AMPs) or de-novo designed analogues for the development of new therapeutic agents against the worldwide alarming threat of multidrug-resistant infections.  In contrast with traditional antibiotics, amphibian skin AMPs have: (i) a rapid killing mechanism based on the perturbation of the microbial plasma-membrane, causing irreparable damage that hardly induces resistance; (ii) an anti-biofilm activity and (iii) additional biological properties including the neutralization of the toxic effect of the bacterial lipopolysaccharide as well as the promotion of wound healing activity.

In the past years, a frog-skin derived peptide i.e. Esc(1-21) was found to display a significant in vivo efficacy in a mouse model of keratitis induced by the bacterium Pseudomonas aeruginosa. So far only a few in vivo experiments have provided signs of clinical benefit of AMPs against keratitis. At the same time, it was discovered how the presence of only two L-to D amino acids substitution within Esc(1-21) is sufficient to improve the peptide’s selectivity index, biostability, wound healing activity and in vivo therapeutic efficacy. In parallel, it was found that this selective epimerization can affect the peptide’s ability to interact with the bacterial lipopolysaccharide (LPS) or model membranes (liposomes) as well as with nucleotides (i.e. guanosine pentaphosphate, ppGpp) preventing biofilm formation. However, a key step for AMPs development is a proper delivery system to target them at the site of infection at effective concentration, with minimal off-target effects. In this context, by means of nanotechnology approaches, it was demonstrated how encapsulation of these peptides inside engineered biodegradable polymeric nanoparticles is an excellent strategy (i) to overcome lung barriers (i.e. the sticky mucus lying the airways epithelia, mostly in cystic fibrosis sufferers) that usually interfere with the antibiotic treatment and (ii) to prolong the antimicrobial efficacy of the encapsulated peptide.

Consistent with the above goals, the main objectives of my current scientific research include:

• The development of new inhalable formulations to optimize the pulmonary delivery of peptides and to provide their controlled release over time;
• The development of antimicrobial medical devices, such as peptide-immobilized contact lenses, to prevent microbial colonization of the lenses and the incidence of ocular surface infections.
•  The development of peptide-based nano-formulations to apply locally in a suitable solution or using nanoparticulate systems, in order to accelerate wound-healing of the corneal/bronchial epithelium or the skin.
• Design and characterization of peptide analogs for SAR studies

Finally, by using experimental conditions that allow both the determination of microbicidal activity and the measurement of peptide/membrane association directly in bacteria, the gap between biological and physicochemical studies was filled and the amount of cell-bound peptide molecules needed for killing a bacterium for identified. Studies aimed at assessing the exact site of association of peptides to bacterial cells are in progress.