<p>Antimicrobial Peptide-Loaded Nanoparticles as Inhalation Therapy for <em>Pseudomonas aeruginosa</em> Infections</p>

Abstract

Introduction: Antibiotic-resistant bacteria kill 25,000 people every year in the EU. Patients subject to recurrent lung infections are the most vulnerable to severe or even lethal infections. For these patients, pulmonary delivery of antibiotics would be advantageous, since inhalation can achieve higher concentration in the lungs than iv administration and can provide a faster onset of action. This would allow for the delivery of higher doses and hence reduce the number of treatments required. We report here about a new nanosystem (M33-NS) obtained by capturing SET-M33 peptide on single-chain dextran nanoparticles. SET-M33 is a non-natural antimicrobial peptide synthesized in branched form. This form gives the peptide resistance to degradation in biological fluids. SET-M33 has previously shown efficacy in vitro against about one hundred of Gram-negative multidrug and extensively drug-resistant clinical isolates and was also active in preclinical infection models of pneumonia, sepsis and skin infections. Methods: The new nanosystem was evaluated for its efficacy in bacteria cells and in a mouse model of pneumonia. Toxicity and genotoxicity were also tested in vitro. Biodistribution and pharmacokinetic studies in healthy rats were carried out using a radiolabeled derivative of the nanosystem. Results: The M33-nanosystem, studied here, showed to be effective against Pseudomonas aeruginosa in time-kill kinetic experiments. Cytotoxicity towards different animal cell lines was acceptable. Lung residence time of the antimicrobial peptide, administered via aerosol in healthy rats, was markedly improved by capturing SET-M33 on dextran nanoparticles. M33-NS was also efficient in eradicating pulmonary infection in a BALB/c mouse model of pneumonia caused by P. aeruginosa. Discussion: This study revealed that the encapsulation of the antimicrobial peptide in dextran nanoparticles markedly improved lung residence time of the peptide administered via aerosol. The result has to be considered among the aims of the development of a new therapeutic option for patients suffering recurrent infections, that will benefit from high local doses of persistent antimicrobials.

Antimicrobial and Amyloidogenic Activity of Peptides. Can Antimicrobial Peptides Be Used against SARS-CoV-2?

“…For LL-37 a significant loss of antimicrobial function was shown when the peptide was exposed to carbon nanoparticles at low concentrations, and the interaction of nanomaterials with the peptide led to a significant change in the peptide structure [ 130 ]. Another study showed that encapsulation of the AMP in dextran nanoparticles increases the residence time in the lungs of the peptide administered via aerosol [ 131 ]. In a recent work, the effective localization of natural AMPs on a negatively charged bacterial surface was described using structurally nanoengineered AMP polymers (SNAPPs) [ 132 ].…”

Tribolium castaneum defensin 1 kills Moraxella catarrhalis in an in vitro infection model but does not harm commensal bacteria

“…With M. catarrhalis, we chose an important pathogen with potentially chronic disease manifestation, which we show for the first time to be sensitive to defensin 1 and sarcotoxin 1 C. The clinical implications of AMPs against pathogens of the airways necessitates development of topical application of AMPs to the lung epithelium, which requires the large-scale production of AMPs as aerosol formulations [24]. Recently, successful attempts have been made to neutralize Pseudomonas aeruginosa with AMPs coupled to nanoparticles in a mouse model [25], and also to render AMPs inhalable by spray-drying [26]. In the advent of spreading antibiotics resistance, AMPs hold great potential as successors or support of classical antibiotic treatment.…”

Polymeric Nanoparticles for Antimicrobial Therapies: An up-to-date Overview

“…This approach allows for the specific targeting of S. aureus bacterial strains while reducing the dosage and the system’s toxicity [ 125 ]. Other bioactive compounds that can be used as antimicrobial agents include antimicrobial glycolipids, such as sophorolipids and rhamnolipids encapsulated into chitosan nanoparticles [ 126 ], and antimicrobial peptides, such as the SET-M33 peptide, encapsulated into dextran nanoparticles [ 127 ].…”