Immunomodulatory and Anti-inflammatory Activity in Vitro and in Vivo of a Novel Antimicrobial Candidate

Brunetti, Jlenia; Roscia, Giulia; Lampronti, Ilaria; Gambari, Roberto; Quercini, Leila; Falciani, Chiara; Bracci, Luisa; Pini, Alessandro

doi:10.1074/jbc.m116.750257

Cited by 40 publications

(34 citation statements)

References 27 publications

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“…SET-M33 is a novel AMP, active in vitro and in vivo against Gramnegative bacteria and showing an acceptable toxicity profile on human cells and in mice [5,8,10,33,34]. In this work, we have shown that it can be synergistic with a number of antibiotics of different families (including those that can be administered also by aerosol) against representative strains of MDR/XDR Gram-negative pathogens.…”

Section: Discussionmentioning

confidence: 95%

Synergistic activity profile of an antimicrobial peptide against multidrug‐resistant and extensively drug‐resistant strains of Gram‐negative bacterial pathogens

Pollini

Brunetti

Sennati

et al. 2017

Journal of Peptide Science

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Infection sustained by multidrug-resistant and extensively drug-resistant bacterial pathogens is often untreatable with the standard of care antibiotics, and the combination of anti-infective compounds often represents the only therapeutic strategy to face this major clinical treat. SET-M33 is a novel antimicrobial peptide (AMP) that has demonstrated in vitro and in vivo antimicrobial activity against Gram-negative bacteria and has shown interesting features in preclinical evaluations. Particularly, it showed efficacy against a number of multidrug-resistant and extensively drug-resistant clinical strains of Gram-negative pathogens, in in vitro and in vivo assessments. Here, we explored the potential synergistic activity of SET-M33 in combination with different standard of care antibiotics by the checkerboard method against a panel of six strains of Gram-negative pathogens including multidrug-resistant and extensively drug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. SET-M33 showed synergistic activity with antibiotics of different families against these clinically relevant strains. A synergistic effect was observed for SET-M33 in combination with rifampin, meropenem, aztreonam, and tobramycin mostly on K. pneumoniae and A. baumannii strains, while the SET-M33 plus ciprofloxacin combination was additive with all tested strains. Synergy was not apparently linked to the bacterial species or phenotype but was rather strain-specific, highlighting the need for individual strain testing for synergistic antimicrobial combinations. These findings extend current knowledge on synergistic activity of AMPs in combination with conventional agents and support the potential role of SET-M33 as a novel therapeutic agent against antibiotic-resistant Gram-negative pathogens. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 95%

Synergistic activity profile of an antimicrobial peptide against multidrug‐resistant and extensively drug‐resistant strains of Gram‐negative bacterial pathogens

Pollini

Brunetti

Sennati

et al. 2017

Journal of Peptide Science

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“…Synthesizing AMP polymers using dendrimer or other AMP nanoparticles to increase the local concentration of the AMP can lower the required dose and combat multidrug-resistant bacteria [133][134][135][136]. (iii) The development of in vitro tests and computational predictions, for example, testing for similarities with allergens, can help to evaluate the immunogenicity and allergenic potential of newly developed AMPs [137], e.g., the basophil activation test [138], cytokine assays [139], lymphocyte activation analysis [140], and Structural Database of Allergenic Proteins (SDAP) [141][142][143]. Although these tools cannot fully predict the allergenic effects of a new AMP in the clinic, they provide a promising preclinical tools for evaluating peptide-based drugs.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Development and Challenges of Antimicrobial Peptides for Therapeutic Applications

2020

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More than 3000 antimicrobial peptides (AMPs) have been discovered, seven of which have been approved by the U.S. Food and Drug Administration (FDA). Now commercialized, these seven peptides have mostly been utilized for topical medications, though some have been injected into the body to treat severe bacterial infections. To understand the translational potential for AMPs, we analyzed FDA-approved drugs in the FDA drug database. We examined their physicochemical properties, secondary structures, and mechanisms of action, and compared them with the peptides in the AMP database. All FDA-approved AMPs were discovered in Gram-positive soil bacteria, and 98% of known AMPs also come from natural sources (skin secretions of frogs and toxins from different species). However, AMPs can have undesirable properties as drugs, including instability and toxicity. Thus, the design and construction of effective AMPs require an understanding of the mechanisms of known peptides and their effects on the human body. This review provides an overview to guide the development of AMPs that can potentially be used as antimicrobial drugs.

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“…7 Like other antimicrobial peptides, 14 SET-M33 also features anti-inflammatory activity. 8 A study dealing with the antimicrobial mechanism of action of SET-M33 demonstrated that after an initial binding to the bacterial cell wall lipopolysaccharide, the peptide interacts with the bacterial membrane and acquires an amphipathic helix structure. This structure may be partially embedded into the membrane, thereby destroying its function and eventually the cell itself.…”

Section: Introductionmentioning

confidence: 99%

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

Falciani

Zevolini

Brunetti

et al. 2020

IJN

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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.

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Immunomodulatory and Anti-inflammatory Activity in Vitro and in Vivo of a Novel Antimicrobial Candidate

Cited by 40 publications

References 27 publications

Synergistic activity profile of an antimicrobial peptide against multidrug‐resistant and extensively drug‐resistant strains of Gram‐negative bacterial pathogens

Synergistic activity profile of an antimicrobial peptide against multidrug‐resistant and extensively drug‐resistant strains of Gram‐negative bacterial pathogens

Development and Challenges of Antimicrobial Peptides for Therapeutic Applications

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

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