Ricerc@Sapienza

Lung infections associated with Staphylococcus aureus and Pseudomonas aeruginosa bacteria represent a major life threat, especially in elderly. This is mainly due to the ability of these pathogens to form biofilms which are very difficult to eradicate by the currently-used antibiotics. In addition, the presence of a compromised immune system related to age, including deficiency of vitamin D, contributes to the establishment of such infections.
Antimicrobial peptides (AMPs) hold promise for the generation of new therapeutics. We identified a short-sized AMP from amphibian skin, Esc(1-21), which rapidly kills these microbes with a membrane-perturbing mechanism. This prevents bacteria from developing resistance. However, some major tasks need to be reached to make AMPs as good candidates for therapy: minimal enzymatic degradation/cytotoxicity and a suitable formulation for peptide delivery. In line with the above, we synthesized a diastereomer of Esc(1-21) by replacing two L-amino acids with the corresponding D-enantiomers. It resulted to be more stable; less toxic to mammalian cells and more efficient in reducing lung bacterial burden. Importantly, before bringing AMPs to clinical use, it is crucial the development of pharmaceutical formulations to assist peptide diffusion through extracellular barriers and to provide a sustained peptide release prolonging its therapeutic efficacy.
In addition, combination therapy of AMPs with traditional antibiotics is a valuable strategy to maximize the efficacy of single drugs and to reduce the resistance selection pressure.
In this Project, we will properly evaluate:
- the biochemical/biological properties of selected AMPs (i.e. temporins and Esc-peptides) in lung mimicking environment;
- the synergistic effect with conventional antibiotics, suitably selected by a novel software tool;
- the efficacy in lung bacterial clearance;
- the in vitro and in vivo efficacy of polymeric nanoparticles for lung delivery of AMPs.