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Wide-spectrum biomimetic antimicrobial systems

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      ABSTRACT

      Antimicrobial peptides (AMPs) are effective components of the host immune response and are widely distributed throughout nature. Recently, nontoxic antimicrobial polymers that mimic the structures of naturally occurring AMPs have been designed and are under development commercially as novel therapeutics. These compounds have several potential advantages over natural AMPs, including greater stability and reduced immunogenicity compared to natural peptides, relatively simple and scalable syntheses and the ability to tailor or “fine tune” their activities through combinatorial approaches. In previous work, we demonstrated the utility of certain generally regarded as safe (GRAS) flavorant and aroma compounds as enhancers of uptake and activity of clinically important antibiotics (Brehm-Stecher & Johnson, 2003). Here, we have extended this approach to include enhancement of biomimetic antimicrobial polymers. Three low molecular weight (<1000 D), broad-spectrum arylamide polymers (PolyMedix, Inc., Radnor, PA) were examined for their antimicrobial activities against gram-negative bacteria, gram-positive bacteria, yeast and filamentous fungi, both alone and when co-administered with sesquiterpenoid enhancers. Assay formats included disk diffusion, automated turbidimetry, time course (kinetic) plating of antimicrobial-treated cell suspensions, outer membrane assays with 1-N-phenylnaphthylamine (NPN) and transmission electron microscopy (TEM). Although results differed according to the polymer and test organism used, treatments containing sesquiterpenoids were marked by either increased ZOIs, decreased MICs or more rapid inactivation when compared with polymer-only treatments. Antimicrobial activity, expressed as decimal reduction times (D-value), showed that after 5 min, the combination of sesquiterpenoid and polymer was significantly different from the controls (p < 0.05) with a D-value of 3.92 min when incubated with Escherichia coli ATCC 25922. Collectively, our results indicate that the combination of sesquiterpenoid-enhancing agents with biomimetic antimicrobial polymers shows promise for the development of new, faster-acting and more broadly effective antimicrobial therapies.

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      Most cited references 23

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      Antimicrobial peptides of multicellular organisms.

      Multicellular organisms live, by and large, harmoniously with microbes. The cornea of the eye of an animal is almost always free of signs of infection. The insect flourishes without lymphocytes or antibodies. A plant seed germinates successfully in the midst of soil microbes. How is this accomplished? Both animals and plants possess potent, broad-spectrum antimicrobial peptides, which they use to fend off a wide range of microbes, including bacteria, fungi, viruses and protozoa. What sorts of molecules are they? How are they employed by animals in their defence? As our need for new antibiotics becomes more pressing, could we design anti-infective drugs based on the design principles these molecules teach us?
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        Mechanisms of antimicrobial peptide action and resistance.

        Antimicrobial peptides have been isolated and characterized from tissues and organisms representing virtually every kingdom and phylum, ranging from prokaryotes to humans. Yet, recurrent structural and functional themes in mechanisms of action and resistance are observed among peptides of widely diverse source and composition. Biochemical distinctions among the peptides themselves, target versus host cells, and the microenvironments in which these counterparts convene, likely provide for varying degrees of selective toxicity among diverse antimicrobial peptide types. Moreover, many antimicrobial peptides employ sophisticated and dynamic mechanisms of action to effect rapid and potent activities consistent with their likely roles in antimicrobial host defense. In balance, successful microbial pathogens have evolved multifaceted and effective countermeasures to avoid exposure to and subvert mechanisms of antimicrobial peptides. A clearer recognition of these opposing themes will significantly advance our understanding of how antimicrobial peptides function in defense against infection. Furthermore, this understanding may provide new models and strategies for developing novel antimicrobial agents, that may also augment immunity, restore potency or amplify the mechanisms of conventional antibiotics, and minimize antimicrobial resistance mechanisms among pathogens. From these perspectives, the intention of this review is to illustrate the contemporary structural and functional themes among mechanisms of antimicrobial peptide action and resistance.
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          Agents that increase the permeability of the outer membrane.

          The outer membrane of gram-negative bacteria provides the cell with an effective permeability barrier against external noxious agents, including antibiotics, but is itself a target for antibacterial agents such as polycations and chelators. Both groups of agents weaken the molecular interactions of the lipopolysaccharide constituent of the outer membrane. Various polycations are able, at least under certain conditions, to bind to the anionic sites of lipopolysaccharide. Many of these disorganize and cross the outer membrane and render it permeable to drugs which permeate the intact membrane very poorly. These polycations include polymyxins and their derivatives, protamine, polymers of basic amino acids, compound 48/80, insect cecropins, reptilian magainins, various cationic leukocyte peptides (defensins, bactenecins, bactericidal/permeability-increasing protein, and others), aminoglycosides, and many more. However, the cationic character is not the sole determinant required for the permeabilizing activity, and therefore some of the agents are much more effective permeabilizers than others. They are useful tools in studies in which the poor permeability of the outer membrane poses problems. Some of them undoubtedly have a role as natural antibiotic substances, and they or their derivatives might have some potential as pharmaceutical agents in antibacterial therapy as well. Also, chelators (such as EDTA, nitrilotriacetic acid, and sodium hexametaphosphate), which disintegrate the outer membrane by removing Mg2+ and Ca2+, are effective and valuable permeabilizers.
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            Author and article information

            Affiliations
            Rapid Microbial Detection and Control Laboratory, Department of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011, USA
            Author notes
            [* ]Corresponding author’s e-mail address: byron@ 123456iastate.edu
            Contributors
            (View ORCID Profile)
            Journal
            SOR-LIFE
            ScienceOpen Research
            ScienceOpen
            2199-1006
            29 December 2016
            : 0 (ID: )
            : 0
            : 1-9
            201701
            10.14293/S2199-1006.1.SOR-LIFE.CMGPSN.v1
            © 2017 Wright and Brehm-Stecher

            This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

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