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418 KiB

Open AccessArticle

Antibacterial Activity of Four Human Beta-Defensins: HBD-19, HBD-23, HBD-27, and HBD-29

by Bryan T. Chow, Maira Soto, Bonnie L. Lo, David C. Crosby and David Camerini

Polymers 2012, 4(1), 747-758; https://doi.org/10.3390/polym4010747 - 1 Mar 2012

Cited by 7 | Viewed by 8079

Abstract

Human β-defensins (HBD) are a family of small antimicrobial peptides that play important roles in the innate and adaptive immune defenses against microbial infection. In this study, we predicted the mature sequences and assessed the antibacterial properties of synthetic HBD-19, HBD-23, HBD-27, and [...] Read more.

Human β-defensins (HBD) are a family of small antimicrobial peptides that play important roles in the innate and adaptive immune defenses against microbial infection. In this study, we predicted the mature sequences and assessed the antibacterial properties of synthetic HBD-19, HBD-23, HBD-27, and HBD-29 against three species of clinically relevant bacteria: Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. We also examined the cytotoxicity of each β-defensin to human cells. HBD-19 exhibited modest antibacterial effects against E. coli and S. aureus but had little effect on the growth of P. aeruginosa. HBD-23 exhibited substantial antibacterial effects against all three bacterial species and was particularly potent against the Gram-negative species, E. coli and P. aeruginosa. HBD-27 exerted modest antibacterial activity only towards S. aureus while HBD-29 had modest antibacterial activity for E. coli and P. aeruginosa. HBD-23 and HBD-27 showed little or no toxicity to human peripheral blood mononuclear cells, while HBD-19 and HBD-29 decreased cell viability by 20% at 30 μg/mL. Full article

(This article belongs to the Special Issue Antibacterial Polymers: From Natural Inspiration to Practical Applications)

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559 KiB

Open AccessArticle

Effects of D-Lysine Substitutions on the Activity and Selectivity of Antimicrobial Peptide CM15

by Heather M. Kaminski and Jimmy B. Feix

Polymers 2011, 3(4), 2088-2106; https://doi.org/10.3390/polym3042088 - 6 Dec 2011

Cited by 27 | Viewed by 6800

Abstract

Despite their potent antimicrobial activity, the usefulness of antimicrobial peptides (AMPs) as antibiotics has been limited by their toxicity to eukaryotic cells and a lack of stability in vivo. In the present study we examined the effects of introducing D-lysine residues into [...] Read more.

Despite their potent antimicrobial activity, the usefulness of antimicrobial peptides (AMPs) as antibiotics has been limited by their toxicity to eukaryotic cells and a lack of stability in vivo. In the present study we examined the effects of introducing D-lysine residues into a 15-residue hybrid AMP containing residues 1–7 of cecropin A and residues 2–9 of melittin (designated CM15). Diastereomeric analogs of CM15 containing between two and five D-lysine substitutions were evaluated for their antimicrobial activity, lysis of human erythrocytes, toxicity to murine macrophages, ability to disrupt cell membranes, and protease stability. All of the analogs caused rapid permeabilization of the Staphylococcus aureus cell envelope, as indicated by uptake of SYTOX green. Permeabilization of the plasma membrane of RAW264.7 macrophages was also observed for CM15, but this was substantially diminished for the D-lysine containing analogs. The introduction of D-lysine caused moderate decreases in antimicrobial activity for all analogs studied, with a much more pronounced reduction in toxicity to eukaryotic cells, leading to marked improvements in antimicrobial efficacy. Circular dichroism studies indicated a progressive loss of helical secondary structure upon introduction of D-lysine residues, with a good correspondence between helical content and eukaryotic cell cytotoxicity. Overall, these studies indicate that disruption of amphipathic secondary structure reduces both antimicrobial activity and eukaryotic cell toxicity, but that the reduction in eukaryotic cell cytotoxicity is more pronounced, leading to an overall gain in antimicrobial selectivity. Full article

(This article belongs to the Special Issue Antibacterial Polymers: From Natural Inspiration to Practical Applications)

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477 KiB

Open AccessArticle

Activity and Mechanism of Antimicrobial Peptide-Mimetic Amphiphilic Polymethacrylate Derivatives

by Iva Sovadinova, Edmund F. Palermo, Michael Urban, Philomene Mpiga, Gregory A. Caputo and Kenichi Kuroda

Polymers 2011, 3(3), 1512-1532; https://doi.org/10.3390/polym3031512 - 13 Sep 2011

Cited by 83 | Viewed by 11463

Abstract

Cationic amphiphilic polymethacrylate derivatives (PMAs) have shown potential as a novel class of synthetic antimicrobials. A panel of PMAs with varied ratios of hydrophobic and cationic side chains were synthesized and tested for antimicrobial activity and mechanism of action. The PMAs are shown [...] Read more.

Cationic amphiphilic polymethacrylate derivatives (PMAs) have shown potential as a novel class of synthetic antimicrobials. A panel of PMAs with varied ratios of hydrophobic and cationic side chains were synthesized and tested for antimicrobial activity and mechanism of action. The PMAs are shown to be active against a panel of pathogenic bacteria, including a drug-resistant Staphylococcus aureus, compared to the natural antimicrobial peptide magainin which did not display any activity against the same strain. The selected PMAs with 47–63% of methyl groups in the side chains showed minimum inhibitory concentrations of ≤2–31 µg/mL, but cause only minimal harm to human red blood cells. The PMAs also exhibit rapid bactericidal kinetics. Culturing Escherichia coli in the presence of the PMAs did not exhibit any potential to develop resistance against the PMAs. The antibacterial activities of PMAs against E. coli and S. aureus were slightly reduced in the presence of physiological salts. The activity of PMAs showed bactericidal effects against E. coli and S. aureus in both exponential and stationary growth phases. These results demonstrate that PMAs are a new antimicrobial platform with no observed development of resistance in bacteria. In addition, the PMAs permeabilized the E. coli outer membrane at polymer concentrations lower than their MIC values, but they did not show any effect on the bacterial inner membrane. This indicates that mechanisms other than membrane permeabilization may be the primary factors determining their antimicrobial activity. Full article

(This article belongs to the Special Issue Antibacterial Polymers: From Natural Inspiration to Practical Applications)

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784 KiB

Open AccessArticle

Activity and Export of Engineered Nisin-(1-22) Analogs

by Annechien Plat, Anneke Kuipers, Jacobien G. de Lange, Gert N. Moll and Rick Rink

Polymers 2011, 3(3), 1282-1296; https://doi.org/10.3390/polym3031282 - 12 Aug 2011

Cited by 13 | Viewed by 7597

Abstract

The pentacyclic peptide antibiotic nisin, produced by Lactococcus lactis is ubiquitously applied as a food preservative. We previously demonstrated that the truncated nisin-(1-22) has only 10-fold lower activity than nisin. Here we aimed at further developing this tricyclic nisin analog to reach activity [...] Read more.

The pentacyclic peptide antibiotic nisin, produced by Lactococcus lactis is ubiquitously applied as a food preservative. We previously demonstrated that the truncated nisin-(1-22) has only 10-fold lower activity than nisin. Here we aimed at further developing this tricyclic nisin analog to reach activity comparable to that of nisin. Our data demonstrate that: (1) ring A has a large mutational freedom; (2) the composition of residues 20–22 strongly affects production levels of nisin-(1-22); (3) a positively charged C-terminus of nisin-(1-22) significantly enhances its antimicrobial activity; (4) nisin-(1-22) inhibits in vitro growth of a target strain using different dynamics than nisin. Full article

(This article belongs to the Special Issue Antibacterial Polymers: From Natural Inspiration to Practical Applications)

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657 KiB

Open AccessArticle

Dark Antimicrobial Mechanisms of Cationic Phenylene Ethynylene Polymers and Oligomers against Escherichia coli

by Ying Wang, Zhijun Zhou, Jingshu Zhu, Yanli Tang, Taylor D. Canady, Eva Y. Chi, Kirk S. Schanze and David G. Whitten

Polymers 2011, 3(3), 1199-1214; https://doi.org/10.3390/polym3031199 - 29 Jul 2011

Cited by 43 | Viewed by 11053

Abstract

The interactions of poly(phenylene ethynylene) (PPE)-based cationic conjugated polyelectrolytes (CPEs) and oligo-phenylene ethynylenes (OPEs) with E. coli cells are investigated to gain insights into the differences in the dark killing mechanisms between CPEs and OPEs. A laboratory strain of E. coli with antibiotic [...] Read more.

The interactions of poly(phenylene ethynylene) (PPE)-based cationic conjugated polyelectrolytes (CPEs) and oligo-phenylene ethynylenes (OPEs) with E. coli cells are investigated to gain insights into the differences in the dark killing mechanisms between CPEs and OPEs. A laboratory strain of E. coli with antibiotic resistance is included in this work to study the influence of antibiotic resistance on the antimicrobial activity of the CPEs and OPEs. In agreement with our previous findings, these compounds can efficiently perturb the bacterial cell wall and cytoplasmic membrane, resulting in bacterial cell death. Electron microscopy imaging and cytoplasmic membrane permeability assays reveal that the oligomeric OPEs penetrate the bacterial outer membrane and interact efficiently with the bacterial cytoplasmic membrane. In contrast, the polymeric CPEs cause serious damage to the cell surface. In addition, the minimum inhibitory concentration (MIC) and hemolytic concentration (HC) of the CPEs and OPEs are also measured to compare their antimicrobial activities against two different strains of E. coli with the compounds’ toxicity levels against human red blood cells (RBC). MIC and HC measurements are in good agreement with our previous model membrane perturbation study, which reveals that the different membrane perturbation abilities of the CPEs and OPEs are in part responsible for their selectivity towards bacteria compared to mammalian cells. Our study gives insight to several structural features of the PPE-based CPEs and OPEs that modulate their antimicrobial properties and that these features can serve as a basis for further tuning their structures to optimize antimicrobial properties. Full article

(This article belongs to the Special Issue Antibacterial Polymers: From Natural Inspiration to Practical Applications)

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Review

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1401 KiB

Open AccessReview

Human Defensins: Potential Tools for Clinical Applications

by Jochen Winter and Matthias Wenghoefer

Polymers 2012, 4(1), 691-709; https://doi.org/10.3390/polym4010691 - 28 Feb 2012

Cited by 36 | Viewed by 11373

Abstract

As components of the innate immune system, antimicrobial peptides in the form of human defensins play an important role in host defense by serving as the epithelial layer’s biochemical barrier against local infections. Recent studies have shown these molecules to have far more [...] Read more.

As components of the innate immune system, antimicrobial peptides in the form of human defensins play an important role in host defense by serving as the epithelial layer’s biochemical barrier against local infections. Recent studies have shown these molecules to have far more additional cellular functions besides their antimicrobial activity. Defensins play a role in cell division, attraction and maturation of immune cells, differentiation and reorganization of epithelial tissues, wound healing and tumor suppression. This multitude of function makes human defensins appear to be excellent tools for therapeutic approaches. These antimicrobial peptides may be used directly as a remedy against bacterial and viral infections. Furthermore, the application of human defensins can be used to promote wound healing and epithelial reorganization. In particular, human β-defensins have a strong impact on osteoblast proliferation and differentiation. Human β-defensins have already been applied as a vaccination against HIV-1. Another potentially useful characteristic of defensins is their suitability as diagnostic markers in cancer therapy. In particular, α-defensins have already been used for this purpose. Human α-defensin-3, for example, has been described as a tumor marker for lymphocytes. High gene expression levels of α-defensin-3 and -4 have been detected in benign oral neoplasia, α-defensin-6 is considered to be a tumor marker for colon cancer. Full article

(This article belongs to the Special Issue Antibacterial Polymers: From Natural Inspiration to Practical Applications)

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173 KiB

Open AccessReview

Role of Antimicrobial Peptides in Inflammatory Bowel Disease

by Jan-Michel Otte and Stefan Vordenbäumen

Polymers 2011, 3(4), 2010-2017; https://doi.org/10.3390/polym3042010 - 16 Nov 2011

Cited by 15 | Viewed by 6673

Abstract

Inflammatory bowel diseases (IBD) are characterized by a chronic relapsing inflammation of the gastrointestinal mucosa. The etiology and pathogenesis of these disorders such as Crohn’s disease and ulcerative colitis are incompletely understood. Recently, antimicrobial peptides, which are expressed by leukocytes and epithelia, have [...] Read more.

Inflammatory bowel diseases (IBD) are characterized by a chronic relapsing inflammation of the gastrointestinal mucosa. The etiology and pathogenesis of these disorders such as Crohn’s disease and ulcerative colitis are incompletely understood. Recently, antimicrobial peptides, which are expressed by leukocytes and epithelia, have been implicated in the pathogenesis of IBD. Antimicrobial peptides are pivotal for intestinal defense, shaping the composition of the luminal flora and contributing thereby to the maintenance of intestinal homeostasis. Apart from their antimicrobial activity affecting commensal bacteria, immunomodulatory properties of antimicrobial peptides have been identified, which link innate and adaptive immune response. There is increasing evidence that alterations in mucosal levels of these peptides contribute to IBD pathogenensis. Full article

(This article belongs to the Special Issue Antibacterial Polymers: From Natural Inspiration to Practical Applications)

192 KiB

Open AccessReview

Defensins: Potential Effectors in Autoimmune Rheumatic Disorders

by Stefan Vordenbäumen and Matthias Schneider

Polymers 2011, 3(3), 1268-1281; https://doi.org/10.3390/polym3031268 - 11 Aug 2011

Cited by 9 | Viewed by 7159

Abstract

Defensins are small cationic peptides with antimicrobial properties. They constitute a highly conserved innate immune defense mechanism across species. Based on the arrangement of disulfide-bonds, α- and β-defensins are distinguished in humans. Both types of defensin comprise several distinct molecules that are preferentially [...] Read more.

Defensins are small cationic peptides with antimicrobial properties. They constitute a highly conserved innate immune defense mechanism across species. Based on the arrangement of disulfide-bonds, α- and β-defensins are distinguished in humans. Both types of defensin comprise several distinct molecules that are preferentially expressed at epithelial surfaces and in blood cells. In the last decade, multiple immunomodulatory functions of defensins have been recognized, including chemotactic activity, the promotion of antigen presentation, and modulations of proinflammatory cytokine secretion. These findings suggested a role for defensins not only as a first line of defense, but also as connectors of innate and adaptive immune responses. Recently, increasingly accumulating evidence has indicated that defensins may also be involved in the pathogenesis of autoimmune rheumatic disorders such as systemic lupus erythematosus and rheumatoid arthritis. The current review summarizes the data connecting defensins to autoimmunity. Full article

(This article belongs to the Special Issue Antibacterial Polymers: From Natural Inspiration to Practical Applications)

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