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      Antibacterial Peptide-Based Gel for Prevention of Medical Implanted-Device Infection

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          Abstract

          Implanted medical devices are prone to infection. Designing new strategies to reduce infection and implant rejection are an important challenge for modern medicine. To this end, in the last few years many hydrogels have been designed as matrices for antimicrobial molecules destined to fight frequent infection found in moist environments like the oral cavity. In this study, two types of original hydrogels containing the antimicrobial peptide Cateslytin have been designed. The first hydrogel is based on alginate modified with catechol moieties (AC gel). The choice of these catechol functional groups which derive from mussel’s catechol originates from their strong adhesion properties on various surfaces. The second type of gel we tested is a mixture of alginate catechol and thiol-terminated Pluronic (AC/PlubisSH), a polymer derived from Pluronic, a well-known biocompatible polymer. This PlubisSH polymer has been chosen for its capacity to enhance the cohesion of the composition. These two gels offer new clinical uses, as they can be injected and jellify in a few minutes. Moreover, we show these gels strongly adhere to implant surfaces and gingiva. Once gelled, they demonstrate a high level of rheological properties and stability. In particular, the dissipative energy of the (AC/PlubisSH) gel detachment reaches a high value on gingiva (10 J.m -2) and on titanium alloys (4 J.m -2), conferring a strong mechanical barrier. Moreover, the Cateslytin peptide in hydrogels exhibited potent antimicrobial activities against P. gingivalis, where a strong inhibition of bacterial metabolic activity and viability was observed, indicating reduced virulence. Gel biocompatibility tests indicate no signs of toxicity. In conclusion, these new hydrogels could be ideal candidates in the prevention and/or management of periimplant diseases.

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          The expanding scope of antimicrobial peptide structures and their modes of action.

          Antimicrobial peptides (AMPs) are an integral part of the innate immune system that protect a host from invading pathogenic bacteria. To help overcome the problem of antimicrobial resistance, cationic AMPs are currently being considered as potential alternatives for antibiotics. Although extremely variable in length, amino acid composition and secondary structure, all peptides can adopt a distinct membrane-bound amphipathic conformation. Recent studies demonstrate that they achieve their antimicrobial activity by disrupting various key cellular processes. Some peptides can even use multiple mechanisms. Moreover, several intact proteins or protein fragments are now being shown to have inherent antimicrobial activity. A better understanding of the structure-activity relationships of AMPs is required to facilitate the rational design of novel antimicrobial agents. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Antimicrobial Peptides

            The rapid increase in drug-resistant infections has presented a serious challenge to antimicrobial therapies. The failure of the most potent antibiotics to kill “superbugs” emphasizes the urgent need to develop other control agents. Here we review the history and new development of antimicrobial peptides (AMPs), a growing class of natural and synthetic peptides with a wide spectrum of targets including viruses, bacteria, fungi, and parasites. We summarize the major types of AMPs, their modes of action, and the common mechanisms of AMP resistance. In addition, we discuss the principles for designing effective AMPs and the potential of using AMPs to control biofilms (multicellular structures of bacteria embedded in extracellular matrixes) and persister cells (dormant phenotypic variants of bacterial cells that are highly tolerant to antibiotics).
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              Human Antimicrobial Peptides and Proteins

              As the key components of innate immunity, human host defense antimicrobial peptides and proteins (AMPs) play a critical role in warding off invading microbial pathogens. In addition, AMPs can possess other biological functions such as apoptosis, wound healing, and immune modulation. This article provides an overview on the identification, activity, 3D structure, and mechanism of action of human AMPs selected from the antimicrobial peptide database. Over 100 such peptides have been identified from a variety of tissues and epithelial surfaces, including skin, eyes, ears, mouths, gut, immune, nervous and urinary systems. These peptides vary from 10 to 150 amino acids with a net charge between −3 and +20 and a hydrophobic content below 60%. The sequence diversity enables human AMPs to adopt various 3D structures and to attack pathogens by different mechanisms. While α-defensin HD-6 can self-assemble on the bacterial surface into nanonets to entangle bacteria, both HNP-1 and β-defensin hBD-3 are able to block cell wall biosynthesis by binding to lipid II. Lysozyme is well-characterized to cleave bacterial cell wall polysaccharides but can also kill bacteria by a non-catalytic mechanism. The two hydrophobic domains in the long amphipathic α-helix of human cathelicidin LL-37 lays the basis for binding and disrupting the curved anionic bacterial membrane surfaces by forming pores or via the carpet model. Furthermore, dermcidin may serve as ion channel by forming a long helix-bundle structure. In addition, the C-type lectin RegIIIα can initially recognize bacterial peptidoglycans followed by pore formation in the membrane. Finally, histatin 5 and GAPDH(2-32) can enter microbial cells to exert their effects. It appears that granulysin enters cells and kills intracellular pathogens with the aid of pore-forming perforin. This arsenal of human defense proteins not only keeps us healthy but also inspires the development of a new generation of personalized medicine to combat drug-resistant superbugs, fungi, viruses, parasites, or cancer. Alternatively, multiple factors (e.g., albumin, arginine, butyrate, calcium, cyclic AMP, isoleucine, short-chain fatty acids, UV B light, vitamin D, and zinc) are able to induce the expression of antimicrobial peptides, opening new avenues to the development of anti-infectious drugs.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                14 December 2015
                2015
                : 10
                : 12
                : e0145143
                Affiliations
                [1 ]Institut National de la Santé Et de la Recherche Médicale, Unité Mixte de Recherche-S 1121, Biomatériaux et Bioingénierie, Strasbourg, France
                [2 ]Faculté de Chirurgie Dentaire, Université de Strasbourg, Strasbourg, France
                [3 ]Institut Charles Sadron, Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg, France
                [4 ]Institut de Science des Matériaux de Mulhouse, Centre National de la Recherche Scientifique LRC 7228, Mulhouse, France
                Academia Sinica, TAIWAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MM SB MN PS PL OE. Performed the experiments: MM SB MN. Analyzed the data: MM SB VB YH MHMB MN PS PL OE. Contributed reagents/materials/analysis tools: TG LJ MHMB. Wrote the paper: MM SB LJ PS PL OE.

                ‡ These authors are joint senior authors on this work.

                Article
                PONE-D-15-41468
                10.1371/journal.pone.0145143
                4682826
                26659616
                f346cb5b-89f7-4348-ad8f-447382e200e5
                © 2015 Mateescu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 19 September 2015
                : 1 December 2015
                Page count
                Figures: 5, Tables: 0, Pages: 13
                Funding
                This work was supported by Projet MICA Dopaglue ( http://www.instituts-carnot.eu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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