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Antimicrobial Peptides: Development, Conjugation, and Beyond

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A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (30 July 2018) | Viewed by 89736

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Special Issue Editor

Prof. Dr. Suzana K. Straus

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Guest Editor

Department of Chemistry, University of British Columbia, Vancouver, BC V6T 1Z1, Canada
Interests: antimicrobial peptides; viral membrane proteins; biophysical chemistry; NMR; structure-function

Special Issue Information

Dear Colleagues,

Bacterial resistance means that many researchers are looking for alternatives to currently-used antibiotics. One strategy being explored is to use antimicrobial peptides (AMPs). AMPs are considered to be viable alternatives to currently-used antibiotics, because they have a broad antimicrobial spectrum and since bacteria develop little or no resistance towards them. In addition, AMPs are ubiquitous in nature and are involved in the first line of defense in plants and animals.

Although AMPs are promising, only a few are used for systemic therapy. The number of AMPs currently being used is limited because these compounds often display adverse effects such as unknown toxicity against host cells, short circulation half-life due to protease digestion and rapid kidney clearance. To circumvent these issues, a number of strategies are being explored to improve the properties of AMPs via formulations and conjugation to biocompatible polymers. Solutions to the limitation of enzymatic degradation have been investigated by the incorporation of d-amino acids, chemical modification of the peptide (side chain groups, N and C-termini,) cyclization, as well as polymer conjugation. This Special Issue will explore recent advancements in AMP research, as well as the methods to minimize their limitations.

Prof. Dr. Suzana K. Straus
Guest Editor

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Keywords

antimicrobial peptides (AMPs)
biophysical characterization
mode of action
bioconjugation of AMPs
limitation of enzymatic degradation
d-amino acids use in AMPs
cyclization of AMPs
chemical modification of AMPs

Published Papers (6 papers)

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Research

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22 pages, 6591 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Critical Assessment of Methods to Quantify Biofilm Growth and Evaluate Antibiofilm Activity of Host Defence Peptides

by Evan F. Haney, Michael J. Trimble, John T. Cheng, Quentin Vallé and Robert E.W. Hancock

Biomolecules 2018, 8(2), 29; https://doi.org/10.3390/biom8020029 - 21 May 2018

Cited by 168 | Viewed by 18881

Abstract

Biofilms are multicellular communities of bacteria that can adhere to virtually any surface. Bacterial biofilms are clinically relevant, as they are responsible for up to two-thirds of hospital acquired infections and contribute to chronic infections. Troublingly, the bacteria within a biofilm are adaptively resistant to antibiotic treatment and it can take up to 1000 times more antibiotic to kill cells within a biofilm when compared to planktonic bacterial cells. Identifying and optimizing compounds that specifically target bacteria growing in biofilms is required to address this growing concern and the reported antibiofilm activity of natural and synthetic host defence peptides has garnered significant interest. However, a standardized assay to assess the activity of antibiofilm agents has not been established. In the present work, we describe two simple assays that can assess the inhibitory and eradication capacities of peptides towards biofilms that are formed by both Gram-positive and negative bacteria. These assays are suitable for high-throughput workflows in 96-well microplates and they use crystal violet staining to quantify adhered biofilm biomass as well as tetrazolium chloride dye to evaluate the metabolic activity of the biofilms. The effect of media composition on the readouts of these biofilm detection methods was assessed against two strains of Pseudomonas aeruginosa (PAO1 and PA14), as well as a methicillin resistant strain of Staphylococcus aureus. Our results demonstrate that media composition dramatically alters the staining patterns that were obtained with these dye-based methods, highlighting the importance of establishing appropriate biofilm growth conditions for each bacterial species to be evaluated. Confocal microscopy imaging of P. aeruginosa biofilms grown in flow cells revealed that this is likely due to altered biofilm architecture under specific growth conditions. The antibiofilm activity of several antibiotics and synthetic peptides were then evaluated under both inhibition and eradication conditions to illustrate the type of data that can be obtained using this experimental setup. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Development, Conjugation, and Beyond)

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17 pages, 3781 KiB

Open AccessFeature PaperArticle

Improving the Activity of Trp-Rich Antimicrobial Peptides by Arg/Lys Substitutions and Changing the Length of Cationic Residues

by Mauricio Arias, Kathlyn B. Piga, M. Eric Hyndman and Hans J. Vogel

Biomolecules 2018, 8(2), 19; https://doi.org/10.3390/biom8020019 - 19 Apr 2018

Cited by 85 | Viewed by 8459

Abstract

Antimicrobial peptides (AMPs) constitute a promising alternative for the development of new antibiotics that could potentially counteract the growing number of antibiotic-resistant bacteria. However, the AMP structure–function relationships remain unclear and detailed studies are still necessary. The positively charged amino acid residues (Arg and Lys) play a crucial role in the activity of most AMPs due to the promotion of electrostatic interactions between the peptides and bacterial membranes. In this work we have analyzed the antimicrobial and structural properties of several Trp-rich AMPs containing exclusively either Arg or Lys as the positively charged residues. Their antimicrobial activity and mechanism of action were investigated, showing that Lys residues give rise to a reduced antimicrobial potency for most peptides, which was correlated, in turn, with a decrease in their ability to permeabilize the cytoplasmic membrane of Escherichia coli. Additionally, the presence of Arg and Lys renders the peptides susceptible to degradation by proteases, such as trypsin, limiting their therapeutic use. Therefore, modifications of the side chain length of Arg and Lys were investigated in an attempt to improve the protease resistance of AMPs. This approach resulted in enhanced stability to trypsin digestion, and in several cases, shorter sidechains conserved or even improved the antimicrobial activity. All together, these results suggest that Arg-to-Lys substitutions, coupled with side chain length modifications, can be extremely useful for improving the activity and stability of AMPs. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Development, Conjugation, and Beyond)

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Review

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16 pages, 860 KiB

Open AccessReview

Role of Milk-Derived Antibacterial Peptides in Modern Food Biotechnology: Their Synthesis, Applications and Future Perspectives

by Muhammad Usman Khan, Maryam Pirzadeh, Carola Yvette Förster, Sergey Shityakov and Mohammad Ali Shariati

Biomolecules 2018, 8(4), 110; https://doi.org/10.3390/biom8040110 - 05 Oct 2018

Cited by 38 | Viewed by 6042

Abstract

Milk-derived antibacterial peptides (ABPs) are protein fragments with a positive influence on the functions and conditions of a living organism. Milk-derived ABPs have several useful properties important for human health, comprising a significant antibacterial effect against various pathogens, but contain toxic side-effects. These compounds are mainly produced from milk proteins via fermentation and protein hydrolysis. However, they can also be produced using recombinant DNA techniques or organic synthesis. This review describes the role of milk-derived ABPs in modern food biotechnology with an emphasis on their synthesis and applications. Additionally, we also discuss the mechanisms of action and the main bioproperties of ABPs. Finally, we explore future perspectives for improving ABP physicochemical properties and diminishing their toxic side-effects. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Development, Conjugation, and Beyond)

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29 pages, 1640 KiB

Open AccessReview

Antibiofilm Peptides and Peptidomimetics with Focus on Surface Immobilization

by Athina Andrea, Natalia Molchanova and Håvard Jenssen

Biomolecules 2018, 8(2), 27; https://doi.org/10.3390/biom8020027 - 16 May 2018

Cited by 49 | Viewed by 8189

Abstract

Bacterial biofilms pose a major threat to public health, as they are associated with at least two thirds of all infections. They are highly resilient and render conventional antibiotics inefficient. As a part of the innate immune system, antimicrobial peptides have drawn attention within the last decades, as some of them are able to eradicate biofilms at sub-minimum inhibitory concentration (MIC) levels. However, peptides possess a number of disadvantages, such as susceptibility to proteolytic degradation, pH and/or salinity-dependent activity and loss of activity due to binding to serum proteins. Hence, proteolytically stable peptidomimetics were designed to overcome these drawbacks. This paper summarizes the current peptide and peptidomimetic strategies for combating bacteria-associated biofilm infections, both in respect to soluble and surface-functionalized solutions. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Development, Conjugation, and Beyond)

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22 pages, 1084 KiB

Open AccessReview

Biophysical Investigations Elucidating the Mechanisms of Action of Antimicrobial Peptides and Their Synergism

by Arnaud Marquette and Burkhard Bechinger

Biomolecules 2018, 8(2), 18; https://doi.org/10.3390/biom8020018 - 18 Apr 2018

Cited by 85 | Viewed by 8231

Abstract

Biophysical and structural investigations are presented with a focus on the membrane lipid interactions of cationic linear antibiotic peptides such as magainin, PGLa, LL37, and melittin. Observations made with these peptides are distinct as seen from data obtained with the hydrophobic peptide alamethicin. The cationic amphipathic peptides predominantly adopt membrane alignments parallel to the bilayer surface; thus the distribution of polar and non-polar side chains of the amphipathic helices mirror the environmental changes at the membrane interface. Such a membrane partitioning of an amphipathic helix has been shown to cause considerable disruptions in the lipid packing arrangements, transient openings at low peptide concentration, and membrane disintegration at higher peptide-to-lipid ratios. The manifold supramolecular arrangements adopted by lipids and peptides are represented by the ‘soft membranes adapt and respond, also transiently’ (SMART) model. Whereas molecular dynamics simulations provide atomistic views on lipid membranes in the presence of antimicrobial peptides, the biophysical investigations reveal interesting details on a molecular and supramolecular level, and recent microscopic imaging experiments delineate interesting sequences of events when bacterial cells are exposed to such peptides. Finally, biophysical studies that aim to reveal the mechanisms of synergistic interactions of magainin 2 and PGLa are presented, including unpublished isothermal titration calorimetry (ITC), circular dichroism (CD) and dynamic light scattering (DLS) measurements that suggest that the peptides are involved in liposome agglutination by mediating intermembrane interactions. A number of structural events are presented in schematic models that relate to the antimicrobial and synergistic mechanism of amphipathic peptides when they are aligned parallel to the membrane surface. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Development, Conjugation, and Beyond)

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24 pages, 2144 KiB

Open AccessEditor’s ChoiceReview

Antimicrobial Peptides: Diversity, Mechanism of Action and Strategies to Improve the Activity and Biocompatibility In Vivo

by Prashant Kumar, Jayachandran N. Kizhakkedathu and Suzana K. Straus

Biomolecules 2018, 8(1), 4; https://doi.org/10.3390/biom8010004 - 19 Jan 2018

Cited by 705 | Viewed by 38546

Abstract

Antibiotic resistance is projected as one of the greatest threats to human health in the future and hence alternatives are being explored to combat resistance. Antimicrobial peptides (AMPs) have shown great promise, because use of AMPs leads bacteria to develop no or low resistance. In this review, we discuss the diversity, history and the various mechanisms of action of AMPs. Although many AMPs have reached clinical trials, to date not many have been approved by the US Food and Drug Administration (FDA) due to issues with toxicity, protease cleavage and short half-life. Some of the recent strategies developed to improve the activity and biocompatibility of AMPs, such as chemical modifications and the use of delivery systems, are also reviewed in this article. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Development, Conjugation, and Beyond)

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