Respiratory infections associated to bacteria, yeasts, filamentous fungi or to viruses represent a serious life threat, especially in the elderly or in cystic fibrosis (CF) sufferers. This is mainly due to the increasing resistance of these pathogens to commonly-used drugs and, in the case of bacteria and fungi, to their ability to grow in a sessile community (biofilm) that traditional antibiotics/antimycotics are not able to eradicate. In addition, the presence of a compromised immune system related to age, including deficiency of vitamin D (Vd), contributes to the establishment of such infections. Antimicrobial peptides (AMPs) hold promise for the generation of new therapeutics.
Recently, we discovered that the amphibian skin AMPs esculentins and temporins kill both the planktonic and biofilm forms of reference strains of Pseudomonas aeruginosa/Staphylococcus aureus/Candida albicans with a membranolytic mode of action limiting the induction of resistance, while promoting wound healing of the bronchial epithelium. In addition, temporins were found to display a clear activity against the enveloped virus Herpes simplex. However, very little is known about the activity of these AMPs against filamentous fungi or viral species causing infections in the lung of elderly and CF patients.
Hence, with the purpose to develop these AMPs for clinical use as novel therapeutics with antibiotic/antifungal/antiviral and wound healing activities we will conduct: (i) further research studies on their virucidal potency against the most representative viral strains in the respiratory tract (ii) advanced analysis of their activity on a panel of clinical isolates and under physiopathological conditions (iii) an investigation of a potential synergistic effect in combination with conventional drugs and (iv) preclinical studies to evaluate the in vivo safety and efficacy of AMPs in reducing lung microbial/viral load also during Vd deficiency. All these goals fall within the Project aims.
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, for local treatment of bacterial/fungal/viral pulmonary infections, which represent a serious life threat, especially in the elderly and cystic fibrosis sufferers. The achievement of our goals will also contribute to clarify the potency of the selected drug combination in defeating bacterial lung infections also during vitamin D deficiency.
It is widely known that both S. aureus and P. aeruginosa as well as the yeast C. albicans or the filamentous fungi Aspergillus sp. are opportunistic pathogens difficult to eradicate mainly due to their ability to form sessile communities and to be resistant to the available antibiotics/antimycotics. Furthermore, the most common respiratory viruses (influenza, respiratory syncytial virus, rhino and parainfluenza) identified in CF patients and in the elderly, are RNA viruses, for which very few drugs are available and effective, mainly due to the frequent mutations occurring during viral replicative cycle. Therefore, the discovery of new antimicrobials is highly demanded and naturally-occurring AMPs or derivatives hold promise for the generation of a novel class of anti-infective agents.
Overall, our studies will highly contribute to remove the hurdles (e.g. susceptibility to proteolytic degradation, low safety, low bioavailability) that have prevented sofar the adoption of AMPs in clinical settings. Moreover, the use of AMPs in concert with conventional antibiotics/antimycotics 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.
Efforts to develop: (i) amphibian skin AMPs as novel drugs with the ability to treat pulmonary microbial/viral infections; (ii) procedures to evaluate either their structure or efficacy/toxicity in pathophysiological contexts and (iii) to identify the best drug combination therapy for treatment of bacterial/fungal/viral infections will have high potential to bring these molecules closer to clinical use.
Remarkably, the achievement of the Project will likely allow us to identify the best AMP or AMP/drug combination against P. aeruginosa/S. aureus/Candida pneumonia as well as respiratory viruses-related lung dysfunctions and to promote healing of the damaged lung tissue with low risk of inducing resistance. The results of these studies will represent the first step-forward for further development of peptide-based inhalable formulations for an easier and faster administration route in comparison to intravenous injection. This will be of great impact for patients and for small/medium-sized biotech companies that would benefit from the exploitation of this project and likely transfer our technologies to larger pharmaceutical companies for the final clinical translation. The direct economic benefits arising from these industrial applications, however represent only a fraction of the socio-economic impact of adding even a single new component to the declining arsenal of weapons against the sprouting of drug resistance health threat.
Moreover, our Project activities fall within the European Framework Programme for Research and Innovation priorities. Furthermore, the multidisciplinary approach that characterizes this Proposal will allow to integrate resources and knowledge from different fields in order to create a consolidated base for the future advancement of bio-nanomedicine.
Besides being published in peer-reviewed scientific journals and presented at national and international meetings, results achieved from these studies will be disseminated through public meetings also to a wider non-specialist public, to inform people about the risks of antibiotic/antiviral resistance and the measures that can be taken in order to control and to reduce this phenomenon.