The Antimicrobial, Antibiofilm and Anti-Inflammatory Activities of P13#1, a Cathelicidin-like Achiral Peptoid
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Published:2023-09-30
Issue:10
Volume:16
Page:1386
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ISSN:1424-8247
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Container-title:Pharmaceuticals
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language:en
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Short-container-title:Pharmaceuticals
Author:
Cafaro Valeria1ORCID, Bosso Andrea1ORCID, Di Nardo Ilaria1, D’Amato Assunta2ORCID, Izzo Irene2ORCID, De Riccardis Francesco2ORCID, Siepi Marialuisa1, Culurciello Rosanna1, D’Urzo Nunzia1, Chiarot Emiliano3, Torre Antonina3, Pizzo Elio1ORCID, Merola Marcello1ORCID, Notomista Eugenio1
Affiliation:
1. Department of Biology, University of Naples Federico II, 80126 Naples, Italy 2. Department of Chemistry and Biology “A. Zambelli”, University of Salerno, 84084 Fisciano, Italy 3. GSK, 53100 Siena, Italy
Abstract
Cationic antimicrobial peptides (CAMPs) are powerful molecules with antimicrobial, antibiofilm and endotoxin-scavenging activities. These properties make CAMPs very attractive drugs in the face of the rapid increase in multidrug-resistant (MDR) pathogens, but they are limited by their susceptibility to proteolytic degradation. An intriguing solution to this issue could be the development of functional mimics of CAMPs with structures that enable the evasion of proteases. Peptoids (N-substituted glycine oligomers) are an important class of peptidomimetics with interesting benefits: easy synthetic access, intrinsic proteolytic stability and promising bioactivities. Here, we report the characterization of P13#1, a 13-residue peptoid specifically designed to mimic cathelicidins, the best-known and most widespread family of CAMPs. P13#1 showed all the biological activities typically associated with cathelicidins: bactericidal activity over a wide spectrum of strains, including several ESKAPE pathogens; the ability to act in combination with different classes of conventional antibiotics; antibiofilm activity against preformed biofilms of Pseudomonas aeruginosa, comparable to that of human cathelicidin LL-37; limited toxicity; and an ability to inhibit LPS-induced proinflammatory effects which is comparable to that of “the last resource” antibiotic colistin. We further studied the interaction of P13#1 with SDS, LPSs and bacterial cells by using a fluorescent version of P13#1. Finally, in a subcutaneous infection mouse model, it showed antimicrobial and anti-inflammatory activities comparable to ampicillin and gentamicin without apparent toxicity. The collected data indicate that P13#1 is an excellent candidate for the formulation of new antimicrobial therapies.
Funder
Italian Cystic Fibrosis Research Foundation with the contribution of “Delegazione FFC di Imola e Romagna” University of Salerno, FARB Ministero dell’Università e della Ricerca
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine
Reference82 articles.
1. Antimicrobial peptides: The ancient arm of the human immune system;Wiesner;Virulence,2010 2. Host defense peptides: Front-line immunomodulators;Mansour;Trends Immunol.,2014 3. The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms;Riool;Sci. Transl. Med.,2018 4. Efficacy of the antimicrobial peptide TP4 against Helicobacter pylori infection: In vitro membrane perturbation via micellization and in vivo suppression of host immune responses in a mouse model;Narayana;Oncotarget,2015 5. Barreto-Santamaría, A., Rivera, Z.J., García, J.E., Curtidor, H., Patarroyo, M.E., Patarroyo, M.A., and Arévalo-Pinzón, G. (2020). Shorter antibacterial peptide having high selectivity for E. coli membranes and low potential for inducing resistance. Microorganisms, 8.
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