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Antimicrobial Peptides: Therapeutic Potentials

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A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Antimicrobial Agents and Resistance".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 47265

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Dr. Kai Hilpert

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Guest Editor

Institute of Infection and Immunology, St George’s, University of London, London SW17 0RE, UK
Interests: antimicrobial peptides; anticancer peptides; wound healing peptides; diagnostics of mycobacteria; neuro-immunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The WHO has classified antimicrobial resistance as one of the biggest threats to global health, food security, and development today (http://www.who.int/mediacentre/factsheets/antibiotic-resistance/en/). Currently, about 700,000 to 1,000,000 people die worldwide each year because of resistant infections. In the O’Neil Report it is estimated that by 2050 these numbers will increase to 10,000,000, more people than currently killed by cancer. It is estimated that the additional health care cost for this impact will reach US$100 trillion. The situation might even intensify since the number of newly-developed antibiotics is steadily declining. FDA approval of new antimicrobials dropped to three new molecular entities (NME) in this decade. One reason for this is that most major pharmaceutical companies have stalled their research efforts for new antimicrobial compounds. In 1985 more than 30 companies undertook active anti-bacterial programs, whereas in 2013 it was less than 10.

Antimicrobial peptides (AMPs) have been recognised for their ability to kill multidrug resistant bacteria and do not easily induce resistance, two features that makes them very attractive as drug candidates. In addition, the overall peptide drug market is steadily growing, from US$18.9 billion in 2013 to US$23.7 billion in 2020. This has led to improved scale up technologies and new large-scale GMP facilities and innovative drug administration regimes. Supported by the price increase for novel antimicrobials and the “ready to use” technology, antimicrobial peptides can become a viable option for urgently needed new antimicrobial drugs. In the last two decades of AMP research, it became clear that these molecules have multiple biological activities, like antimicrobial, antiparasitic, anticancer and immunomodulatory. In the same time period, multiple targets of AMPs for their antibacterial activities were discovered.

In this Special Issue of Microorganisms, we invite you to send contributions concerning any biological activities related to the therapeutic potential of antimicrobial peptides, including direct (e.g. killing of pathogens/parasites/cancer cells) and indirect (e.g. immunomodulatory effects) modes of action.

Dr. Kai Hilpert
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Antimicrobial peptides
Host defence peptides
Multi-drug resistant bacteria
Novel antimicrobials
Immunomodulation
Immunotherapy
Anticancer peptides
Antiparasitic peptides
Antifungal peptides
Wound healing peptides

Published Papers (11 papers)

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Research

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15 pages, 15489 KiB

Open AccessArticle

Comparison of a Short Linear Antimicrobial Peptide with Its Disulfide-Cyclized and Cyclotide-Grafted Variants against Clinically Relevant Pathogens

by Johannes Koehbach, Jurnorain Gani, Kai Hilpert and David J Craik

Microorganisms 2021, 9(6), 1249; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9061249 - 08 Jun 2021

Cited by 12 | Viewed by 3468

Abstract

According to the World Health Organization (WHO) the development of resistance against antibiotics by microbes is one of the most pressing health concerns. The situation will intensify since only a few pharmacological companies are currently developing novel antimicrobial compounds. Discovery and development of novel antimicrobial compounds with new modes of action are urgently needed. Antimicrobial peptides (AMPs) are known to be able to kill multidrug-resistant bacteria and, therefore, of interest to be developed into antimicrobial drugs. Proteolytic stability and toxicities of these peptides are challenges to overcome, and one strategy frequently used to address stability is cyclization. Here we introduced a disulfide-bond to cyclize a potent and nontoxic 9mer peptide and, in addition, as a proof-of-concept study, grafted this peptide into loop 6 of the cyclotide MCoTI-II. This is the first time an antimicrobial peptide has been successfully grafted onto the cyclotide scaffold. The disulfide-cyclized and grafted cyclotide showed moderate activity in broth and strong activity in 1/5 broth against clinically relevant resistant pathogens. The linear peptide showed superior activity in both conditions. The half-life time in 100% human serum was determined, for the linear peptide, to be 13 min, for the simple disulfide-cyclized peptide, 9 min, and, for the grafted cyclotide 7 h 15 min. The addition of 10% human serum led to a loss of antimicrobial activity for the different organisms, ranging from 1 to >8-fold for the cyclotide. For the disulfide-cyclized version and the linear version, activity also dropped to different degrees, 2 to 18-fold, and 1 to 30-fold respectively. Despite the massive difference in stability, the linear peptide still showed superior antimicrobial activity. The cyclotide and the disulfide-cyclized version demonstrated a slower bactericidal effect than the linear version. All three peptides were stable at high and low pH, and had very low hemolytic and cytotoxic activity. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Therapeutic Potentials)

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24 pages, 4082 KiB

Open AccessArticle

Dual Antimicrobial and Antiproliferative Activity of TcPaSK Peptide Derived from a Tribolium castaneum Insect Defensin

by Aida Robles-Fort, Inmaculada García-Robles, Wasundara Fernando, David W. Hoskin, Carolina Rausell and María Dolores Real

Microorganisms 2021, 9(2), 222; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9020222 - 22 Jan 2021

Cited by 7 | Viewed by 2238

Abstract

Antimicrobial peptides (AMPs) found in the innate immune system of a wide range of organisms might prove useful to fight infections, due to the reported slower development of resistance to AMPs. Increasing the cationicity and keeping moderate hydrophobicity of the AMPs have been described to improve antimicrobial activity. We previously found a peptide derived from the Tribolium castaneum insect defensin 3, exhibiting antrimicrobial activity against several human pathogens. Here, we analyzed the effect against Staphyloccocus aureus of an extended peptide (TcPaSK) containing two additional amino acids, lysine and asparagine, flanking the former peptide fragment in the original insect defensin 3 protein. TcPaSK peptide displayed higher antimicrobial activity against S. aureus, and additionally showed antiproliferative activity against the MDA-MB-231 triple negative breast cancer cell line. A SWATH proteomic analysis revealed the downregulation of proteins involved in cell growth and tumor progression upon TcPaSK cell treatment. The dual role of TcPaSK peptide as antimicrobial and antiproliferative agent makes it a versatile molecule that warrants exploration for its use in novel therapeutic developments as an alternative approach to overcome bacterial antibiotic resistance and to increase the efficacy of conventional cancer treatments. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Therapeutic Potentials)

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14 pages, 1970 KiB

Open AccessArticle

The Anti-Pseudomonal Peptide D-BMAP18 Is Active in Cystic Fibrosis Sputum and Displays Anti-Inflammatory In Vitro Activity

by Margherita Degasperi, Chiara Agostinis, Mario Mardirossian, Massimo Maschio, Andrea Taddio, Roberta Bulla and Marco Scocchi

Microorganisms 2020, 8(9), 1407; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8091407 - 12 Sep 2020

Cited by 5 | Viewed by 2600

Abstract

Most Cystic Fibrosis (CF) patients succumb to airway inflammation and pulmonary infections due to Pseudomonas aeruginosa. D-BMAP18, a membrane-permeabilizing antimicrobial peptide composed of D-amino acids, was evaluated as a possible antibacterial aimed to address this issue. The antipseudomonal activity of D-BMAP18 was tested in a pathophysiological context. The peptide displayed activity against CF isolates of Pseudomonas aeruginosa in the presence of CF sputum when combined with sodium chloride and DNase I. In combination with DNase I, D-BMAP18 discouraged the deposition of new biofilm and eradicated preformed biofilms of some P. aeruginosa strains. In addition, D-BMAP18 down regulated the production of TNF-α, IL1-β, and TGF-β in LPS-stimulated or IFN-γ macrophages derived from THP-1 cells indicating an anti-inflammatory activity. The biocompatibility of D-BMAP18 was assessed using four different cell lines, showing that residual cell-specific cytotoxicity at bactericidal concentrations could be abolished by the presence of CF sputum. Overall, this study suggests that D-BMAP18 may be an interesting molecule as a starting point to develop a novel therapeutic agent to simultaneously contrast lung infections and inflammation in CF patients. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Therapeutic Potentials)

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15 pages, 2143 KiB

Open AccessArticle

Potent Broad-Spectrum Antibacterial Activity of Amphiphilic Peptides against Multidrug-Resistant Bacteria

by Yuan Liu, Jingru Shi, Ziwen Tong, Yuqian Jia, Kangni Yang and Zhiqiang Wang

Microorganisms 2020, 8(9), 1398; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8091398 - 11 Sep 2020

Cited by 13 | Viewed by 2308

Abstract

The emergence and prevalence of multidrug-resistant (MDR) bacteria particularly Gram-negative bacteria presents a global crisis for human health. Colistin and tigecycline were recognized as the last resort of defenses against MDR Gram-negative pathogens. However, the emergence and prevalence of MCR or Tet(X)-mediated acquired drug resistance drastically impaired their clinical efficacy. It has been suggested that antimicrobial peptides might act a crucial role in combating antibiotic resistant bacteria owing to their multiple modes of action and characteristics that are not prone to developing drug resistance. Herein, we report a safe and stable tryptophan-rich amphiphilic peptide termed WRK-12 with broad-spectrum antibacterial activity against various MDR bacteria, including MRSA, colistin and tigecycline-resistant Escherichia coli. Mechanistical studies showed that WRK-12 killed resistant E. coli through permeabilizing the bacterial membrane, dissipating membrane potential and triggering the production of reactive oxygen species (ROS). Meanwhile, WRK-12 significantly inhibited the formation of an E. coli biofilm in a dose-dependent manner. These findings revealed that amphiphilic peptide WRK-12 is a promising drug candidate in the fight against MDR bacteria. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Therapeutic Potentials)

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21 pages, 3377 KiB

Open AccessArticle

Shorter Antibacterial Peptide Having High Selectivity for E. coli Membranes and Low Potential for Inducing Resistance

by Adriana Barreto-Santamaría, Zuly Jenny Rivera, Javier Eduardo García, Hernando Curtidor, Manuel Elkin Patarroyo, Manuel Alfonso Patarroyo and Gabriela Arévalo-Pinzón

Microorganisms 2020, 8(6), 867; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8060867 - 08 Jun 2020

Cited by 6 | Viewed by 3577

Abstract

Antimicrobial peptides (AMPs) have been recognised as a significant therapeutic option for mitigating resistant microbial infections. It has been found recently that Plasmodium falciparum-derived, 20 residue long, peptide 35409 had antibacterial and haemolytic activity, making it an AMP having reduced selectivity, and suggesting that it should be studied more extensively for obtaining new AMPs having activity solely targeting the bacterial membrane. Peptide 35409 was thus used as template for producing short synthetic peptides (<20 residues long) and evaluating their biological activity and relevant physicochemical characteristics for therapeutic use. Four of the sixteen short peptides evaluated here had activity against E. coli without any associated haemolytic effects. The 35409-1 derivative (17 residues long) had the best therapeutic characteristics as it had high selectivity for bacterial cells, stability in the presence of human sera, activity against E. coli multiresistant clinical isolates and was shorter than the original sequence. It had a powerful membranolytic effect and low potential for inducing resistance in bacteria. This peptide’s characteristics highlighted its potential as an alternative for combating infection caused by E. coli multiresistant bacteria and/or for designing new AMPs. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Therapeutic Potentials)

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22 pages, 3732 KiB

Open AccessArticle

Antifungal and Antibiofilm Activities and the Mechanism of Action of Repeating Lysine-Tryptophan Peptides against Candida albicans

by Gopal Ramamourthy, Jonggwan Park, Changho Seo, Hans J. Vogel and Yoonkyung Park

Microorganisms 2020, 8(5), 758; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8050758 - 18 May 2020

Cited by 29 | Viewed by 4356

Abstract

The rapid increase in the emergence of antifungal-resistant Candida albicans strains is becoming a serious health concern. Because antimicrobial peptides (AMPs) may provide a potential alternative to conventional antifungal agents, we have synthesized a series of peptides with a varying number of lysine and tryptophan repeats (KW_n-NH₂). The antifungal activity of these peptides increased with peptide length, but only the longest KW₅ peptide displayed cytotoxicity towards a human keratinocyte cell line. The KW₄ and KW₅ peptides exhibited strong antifungal activity against C. albicans, even under conditions of high-salt and acidic pH, or the addition of fungal cell wall components. Moreover, KW₄ inhibited biofilm formation by a fluconazole-resistant C. albicans strain. Circular dichroism and fluorescence spectroscopy indicated that fungal liposomes could interact with the longer peptides but that they did not release the fluorescent dye calcein. Subsequently, fluorescence assays with different dyes revealed that KW₄ did not disrupt the membrane integrity of intact fungal cells. Scanning electron microscopy showed no changes in fungal morphology, while laser-scanning confocal microscopy indicated that KW₄ can localize into the cytosol of C. albicans. Gel retardation assays revealed that KW₄ can bind to fungal RNA as a potential intracellular target. Taken together, our data indicate that KW₄ can inhibit cellular functions by binding to RNA and DNA after it has been translocated into the cell, resulting in the eradication of C. albicans. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Therapeutic Potentials)

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20 pages, 2124 KiB

Open AccessArticle

Antimicrobial Peptides from Rat-Tailed Maggots of the Drone Fly Eristalis tenax Show Potent Activity against Multidrug-Resistant Gram-Negative Bacteria

by Rolf Hirsch, Jochen Wiesner, Armin Bauer, Alexander Marker, Heiko Vogel, Peter Eugen Hammann and Andreas Vilcinskas

Microorganisms 2020, 8(5), 626; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8050626 - 25 Apr 2020

Cited by 6 | Viewed by 3758

Abstract

The spread of multidrug-resistant Gram-negative bacteria is an increasing threat to human health, because novel compound classes for the development of antibiotics have not been discovered for decades. Antimicrobial peptides (AMPs) may provide a much-needed breakthrough because these immunity-related defense molecules protect many eukaryotes against Gram-negative pathogens. Recent concepts in evolutionary immunology predict the presence of potent AMPs in insects that have adapted to survive in habitats with extreme microbial contamination. For example, the saprophagous and coprophagous maggots of the drone fly Eristalis tenax (Diptera) can flourish in polluted aquatic habitats, such as sewage tanks and farmyard liquid manure storage pits. We used next-generation sequencing to screen the E. tenax immunity-related transcriptome for AMPs that are synthesized in response to the injection of bacterial lipopolysaccharide. We identified 22 AMPs and selected nine for larger-scale synthesis to test their activity against a broad spectrum of pathogens, including multidrug-resistant Gram-negative bacteria. Two cecropin-like peptides (EtCec1-a and EtCec2-a) and a diptericin-like peptide (EtDip) displayed strong activity against the pathogens, even under simulated physiological conditions, and also achieved a good therapeutic window. Therefore, these AMPs could be used as leads for the development of novel antibiotics. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Therapeutic Potentials)

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19 pages, 5567 KiB

Open AccessArticle

Changes in the Ultrastructure of Candida albicans Treated with Cationic Peptides

by Alina Grigor’eva, Alevtina Bardasheva, Anastasiya Tupitsyna, Nariman Amirkhanov, Nina Tikunova, Dmitrii Pyshnyi, Maksim Kleshev and Elena Ryabchikova

Microorganisms 2020, 8(4), 582; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8040582 - 17 Apr 2020

Cited by 8 | Viewed by 2608

Abstract

Candida albicans is becoming increasingly harmful for humans, which determines the need for new effective antifungal preparations. Currently, when testing antifungals, various morphological methods are used, among which transmission electron microscopy (TEM) is not the leading one. In this work, we used TEM to study the submicroscopic changes in C. albicans cells induced by cationic peptides R9F2 and (KFF)3K. Studies were performed on C. albicans-34 strain from the Collection of EMTC of ICBFM SB RAS in logarithmic phase. R9F2 and (KFF)3K showed an antifungal effect (MIC 10 and 20 μM) and suppressed fungal hyphal growth. Semithin and ultrathin sections of fungal suspensions incubated with 10 μM of peptides were studied at regular intervals from 15 min to 24 h. The first target of both peptides was plasmalemma, and its “alignment” was the only common morphological manifestation of their effect. Other changes in the plasmalemma and alteration of the vacuole and cell wall ultrastructure distinctly differed in cells treated with R9F2 and (KFF)3K peptides. In general, our work has shown pronounced differences of the temporal and morphologic characteristics of the effect of peptides, evidently related to their physicochemical properties. The benefit of TEM studies of ultrathin sections for understanding the mechanisms of action of antifungal drugs is shown. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Therapeutic Potentials)

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18 pages, 2714 KiB

Open AccessArticle

The interaction between Carbohydrates and the Antimicrobial Peptide P-113Tri is Involved in the Killing of Candida albicans

by Guan-Yu Lin, Chuan-Fa Chang and Chung-Yu Lan

Microorganisms 2020, 8(2), 299; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8020299 - 21 Feb 2020

Cited by 7 | Viewed by 3167

Abstract

The emergence of drug resistance to Candida albicans is problematic in the clinical setting. Therefore, developing new antifungal drugs is in high demand. Our previous work indicated that the antimicrobial peptide P-113Tri exhibited higher antifungal activity against planktonic cells, biofilm cells, and clinical isolates of Candida species compared to its parental peptide P-113. In this study, we further investigated the difference between these two peptides in their mechanisms against C. albicans. Microscopic examination showed that P-113 rapidly gained access to C. albicans cells. However, most of the P-113Tri remained on the cell surface. Moreover, using a range of cell wall-defective mutants and competition assays, the results indicated that phosphomannan and N-linked mannan in the cell wall are important for peptide binding to C. albicans cells. Furthermore, the addition of exogenous phosphosugars reduced the efficacy of the peptide, suggesting that negatively charged phosphosugars also contributed to the peptide binding to the cell wall polysaccharides. Finally, using a glycan array, P-113Tri, but not P-113, can bind to other glycans commonly present on other microbial and mammalian cells. Together, these results suggest that P-113 and P-113Tri have fundamental differences in their interaction with C. albicans and candidacidal activities. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Therapeutic Potentials)

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9 pages, 3250 KiB

Open AccessArticle

Methods and Challenges of Using the Greater Wax Moth (Galleria mellonella) as a Model Organism in Antimicrobial Compound Discovery

by Athina Andrea, Karen Angeliki Krogfelt and Håvard Jenssen

Microorganisms 2019, 7(3), 85; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms7030085 - 19 Mar 2019

Cited by 36 | Viewed by 4987

Abstract

Among non-mammalian infection model organisms, the larvae of the greater wax moth Galleria mellonella have seen increasing popularity in recent years. Unlike other invertebrate models, these larvae can be incubated at 37 °C and can be dosed relatively precisely. Despite the increasing number of publications describing the use of this model organism, there is a high variability with regard to how the model is produced in different laboratories, with respect to larva size, age, origin, storage, and rest periods, as well as dosing for infection and treatment. Here, we provide suggestions regarding how some of these factors can be approached, to facilitate the comparability of studies between different laboratories. We introduce a linear regression curve correlating the total larva weight to the liquid volume in order to estimate the in vivo concentration of pathogens and the administered drug concentration. Finally, we discuss several other aspects, including in vivo antibiotic stability in larvae, the infection doses for different pathogens and suggest guidelines for larvae selection. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Therapeutic Potentials)

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Review

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31 pages, 4598 KiB

Open AccessReview

Bacteriocins, Antimicrobial Peptides from Bacterial Origin: Overview of Their Biology and Their Impact against Multidrug-Resistant Bacteria

by Alexis Simons, Kamel Alhanout and Raphaël E. Duval

Microorganisms 2020, 8(5), 639; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8050639 - 27 Apr 2020

Cited by 238 | Viewed by 12847

Abstract

Currently, the emergence and ongoing dissemination of antimicrobial resistance among bacteria are critical health and economic issue, leading to increased rates of morbidity and mortality related to bacterial infections. Research and development for new antimicrobial agents is currently needed to overcome this problem. Among the different approaches studied, bacteriocins seem to be a promising possibility. These molecules are peptides naturally synthesized by ribosomes, produced by both Gram-positive bacteria (GPB) and Gram-negative bacteria (GNB), which will allow these bacteriocin producers to survive in highly competitive polymicrobial environment. Bacteriocins exhibit antimicrobial activity with variable spectrum depending on the peptide, which may target several bacteria. Already used in some areas such as agro-food, bacteriocins may be considered as interesting candidates for further development as antimicrobial agents used in health contexts, particularly considering the issue of antimicrobial resistance. The aim of this review is to present an updated global report on the biology of bacteriocins produced by GPB and GNB, as well as their antibacterial activity against relevant bacterial pathogens, and especially against multidrug-resistant bacteria. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Therapeutic Potentials)

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