The bleakest outlook for a "post-antibiotic era" is one in which microbial infections can no longer be cured. The traditional antibiotic pipeline has been exhausted, while antimicrobial resistance has become a multifaceted crisis, imposing a serious threat to global health. There is thus an urgent need for new antimicrobial treatments. Inspired by nature, antimicrobial peptides (AMPs) are gaining attention for their clinical translation, as they present distint advantages compared to conventional antibiotics. AMPs have shown a pivotal role in the innate immune system of living organisms; many of them are evolutionarily conserved with limited propensity to induce resistance. The main goal of this project is to fully characterize and optimize existing AMPs, i.e. esculentin peptides, against the Gram-negative bacterium Pseudomonas aeruginosa, which represents a serious life threat especially in cystic fibrosis sufferers. In fact, in the lung of these patients it grows in a sessile community (biofilm) that traditional antibiotics are not able to eradicate. We propose to pursue an experimental plan aimed at studying the antibiofilm potency of the selected AMPs on a panel of P. aeruginosa strains under conditions that better reflect physiology of the target districts as well as to assess their stability in biological fluids before testing their safety in mice. Furthermore, the project aims at exploring the effect of these AMPs on the host cells that are present at the sites of infection in terms of metabolic and immunomodulatory activities which represent hitherto unexplored aspects. Another relevant objective of the project is the characterization of novel nanoparticulate systems to prolong AMPs lifespan.
If successful, our multidisciplinary approach will allow a deeper understanding of the effectiveness of Esc peptides-based therapeutic formulation for the translation into real-life medicine to fight the current alarming antibiotic-resistant infectious diseases.
The growing ineffectiveness of the antibiotics currently in use to fight bacterial infections has become a major global concern and could result soon in new pandemics that will be difficult to stem without effective replacement drugs. The global economic impact of antibiotic resistance is important as it includes patients, healthcare providers, researchers, pharmaceutical organisations, healthcare businesses and, moreover, national and international policy-makers. For these reasons, any contribution to reducing the progress of antibiotic resistance will bring significant economic and social benefits in the middle and long term. This project aims at developing novel therapeutic approaches based on the usage of amphibian-skin derived AMPs or their optimized analogs, either alone or in combination with conventional drugs, to counter P. aeruginosa pulmonary infections. These latter represent a serious life threat, especially in cystic fibrosis sufferers where the bacterium forms antibiotic-resistant biofilm communities.
Overall, the achievement of the project's aims will significantly increase our knowledge on the therapeutic potential of the selected AMPs, providing a precise evaluation of their efficacy and applicability. Added to this, the project will generate new insight on the effects of AMPs on host cells that are present at the sites of infection, in terms of metabolic and immumodulatory activities, which represent hitherto unexplored aspects. Project activities could lead to the patenting of our molecules, and/or on their combined use, and/or on their formulation for delivery to the target site. Altogether our studies will highly contribute to remove the hurdles (e.g. susceptibility to proteolytic degradation, low safety, low bioavailability) that have prevented so far the adoption of AMPs in clinical settings. Moreover, the use of AMPs in concert with conventional antibiotics will help in slowing down the incidence of resistance in the latter and will present an alternative first line strategy while new antimicrobials are being settled in.
A clearer understanding of the effectiveness of AMPs as new therapeutic agents could persuade pharmaceutical companies, drug discovery investors and other stakeholders that it is worthwhile to place resources into their developments. Efforts to identify and to develop: (i) amphibian skin AMPs as novel anti-infective drugs; (ii) procedures to evaluate either their structure or efficacy/toxicity in pathophysiological contexts and (iii) the best drug combination therapy for treatment of bacterial infections will have high potential to bring these molecules closer to clinical use.
Our experimental approach, besides enhancing the knowledge on the antibiofilm efficacy of peptide-based antimicrobials, will concur to the development of a novel drug-delivery system to be exploited by small/medium-sized biotech companies in innovative products, paving the way to new industrial technologies for the final clinical translation. Our goals fall within the European Framework Programme for Research and Innovation priorities "Many challenges need to be met. Chronic and infectious diseases, pandemic threats and antimicrobial resistance are on the rise" and are in line with the recommendations of the Global Antibiotic Research and Development Partnership that underline the urgency for development of new treatments and the need for the accelerated entry of new antibiotic drugs. The multidisciplinary approach that characterizes this Proposal will allow to integrate resources and knowledge from different fields to create a consolidated base for the future advancement of bio-nanomedicine.
Results achieved from these studies will be published in peer-reviewed scientific journals and will be disseminated through public meetings also to a wider non-specialist public, to inform people about the risks of antibiotic resistance and the measures that can be taken to control and to reduce this phenomenon.