Development of Antimicrobial Peptides from Amphibian

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Antimicrobial Peptides".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 35115

Special Issue Editors


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Guest Editor
Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
Interests: antimicrobial peptides; peptide-membrane interaction; cystic fibrosis; infectious diseases; pneumonia; keratitis; drug development; wound healing; Pseudomonas aeruginosa
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Guest Editor
Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
Interests: bioactive peptides; biological/biochemical characterization of small bioactive molecules; natural products; structure-activity relationship of natural/synthetic bioactive molecules
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since 1987, when Michael Zasloff isolated magainins from skin secretions of the African toad Xenopus laevis, an increasing number of antimicrobial peptides (AMPs) have been identified in different anuran species and studied in detail. As a result, frog skin is now known as one of the richest sources of natural AMPs from different families. In addition to their originally discovered role as key effectors of innate immunity with a primary role in protecting the host from invading noxious microorganisms, they are now known to carry out functions related to host immune modulation, e.g., endotoxin neutralization, chemotaxis, and wound healing activity. Several studies have emphasized the potential for AMPs to be used in the development of new anti-infective agents with expanding properties. Furthermore, in the rapid evolving field of nanotechnology, several approaches have been designed and developed to conjugate the AMPs with nanoparticulate systems to assist peptide delivery to target sites, thus minimizing potential side effects.

This Special Issue aims to present the most recent advances in the development of frog-skin AMPs as alternative compounds to fight against the alarming problem of antibiotic resistance and to be used in clinical settings.

Prof. Dr. Maria Luisa Mangoni
Dr. Bruno Casciaro
Guest Editors

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Keywords

  • antimicrobial peptides
  • antibiotics
  • multidrug resistance
  • nanotechnologies

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Published Papers (10 papers)

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Editorial

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4 pages, 170 KiB  
Editorial
Development of Antimicrobial Peptides from Amphibians
by Maria Luisa Mangoni and Bruno Casciaro
Antibiotics 2020, 9(11), 772; https://doi.org/10.3390/antibiotics9110772 - 4 Nov 2020
Cited by 14 | Viewed by 2448
Abstract
Since the discovery of magainins from the skin secretions of the African toad Xenopus laevis by Michael Zasloff in 1987, an increasing number of antimicrobial peptides (AMPs) has been identified in different anuran species and studied in detail [...] Full article
(This article belongs to the Special Issue Development of Antimicrobial Peptides from Amphibian)

Research

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15 pages, 2349 KiB  
Article
Peptidomic Analysis of Skin Secretions of the Caribbean Frogs Leptodactylus insularum and Leptodactylus nesiotus (Leptodactylidae) Identifies an Ocellatin with Broad Spectrum Antimicrobial Activity
by Gervonne Barran, Jolanta Kolodziejek, Laurent Coquet, Jérôme Leprince, Thierry Jouenne, Norbert Nowotny, J. Michael Conlon and Milena Mechkarska
Antibiotics 2020, 9(10), 718; https://doi.org/10.3390/antibiotics9100718 - 20 Oct 2020
Cited by 13 | Viewed by 3471
Abstract
Ocellatins are peptides produced in the skins of frogs belonging to the genus Leptodactylus that generally display weak antimicrobial activity against Gram-negative bacteria only. Peptidomic analysis of norepinephrine-stimulated skin secretions from Leptodactylus insularum Barbour 1906 and Leptodactylus nesiotus Heyer 1994, collected in the [...] Read more.
Ocellatins are peptides produced in the skins of frogs belonging to the genus Leptodactylus that generally display weak antimicrobial activity against Gram-negative bacteria only. Peptidomic analysis of norepinephrine-stimulated skin secretions from Leptodactylus insularum Barbour 1906 and Leptodactylus nesiotus Heyer 1994, collected in the Icacos Peninsula, Trinidad, led to the purification and structural characterization of five ocellatin-related peptides from L. insularum (ocellatin-1I together with its (1–16) fragment, ocellatin-2I and its (1–16) fragment, and ocellatin-3I) and four ocellatins from L. nesiotus (ocellatin-1N, -2N, -3N, and -4N). While ocellatins-1I, -2I, and -1N showed a typically low antimicrobial potency against Gram-negative bacteria, ocellatin-3N (GIFDVLKNLAKGVITSLAS.NH2) was active against an antibiotic-resistant strain of Klebsiella pneumoniae and reference strains of Escherichia coli, K. pneumoniae, Pseudomonas aeruginosa, and Salmonella typhimurium (minimum inhibitory concentrations (MICs) in the range 31.25–62.5 μM), and was the only peptide active against Gram-positive Staphylococcus aureus (MIC = 31.25 μM) and Enterococcus faecium (MIC = 62.5 μM). The therapeutic potential of ocellatin-3N is limited by its moderate hemolytic activity (LC50 = 98 μM) against mouse erythrocytes. The peptide represents a template for the design of long-acting, non-toxic, and broad-spectrum antimicrobial agents for targeting multidrug-resistant pathogens. Full article
(This article belongs to the Special Issue Development of Antimicrobial Peptides from Amphibian)
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13 pages, 5316 KiB  
Article
Caerin 1 Antimicrobial Peptides that Inhibit HIV and Neisseria May Spare Protective Lactobacilli
by Louise A. Rollins-Smith, Patricia B. Smith, Anna M. Ledeczi, Julia M. Rowe and Laura K. Reinert
Antibiotics 2020, 9(10), 661; https://doi.org/10.3390/antibiotics9100661 - 30 Sep 2020
Cited by 10 | Viewed by 2718
Abstract
Although acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) is a manageable disease for many, it is still a source of significant morbidity and economic hardship for many others. The predominant mode of transmission of HIV/AIDS is sexual intercourse, and [...] Read more.
Although acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) is a manageable disease for many, it is still a source of significant morbidity and economic hardship for many others. The predominant mode of transmission of HIV/AIDS is sexual intercourse, and measures to reduce transmission are needed. Previously, we showed that caerin 1 antimicrobial peptides (AMPs) originally derived from Australian amphibians inhibited in vitro transmission of HIV at relatively low concentrations and had low toxicity for T cells and an endocervical cell line. The use of AMPs as part of microbicidal formulations would expose the vaginal microbiome to these agents and cause potential harm to protective lactobacilli. Here, we tested the effects of caerin 1 peptides and their analogs on the viability of two species of common vaginal lactobacilli (Lactobacillus rhamnosus and Lactobacillus crispatus). Several candidate peptides had limited toxicity for the lactobacilli at a range of concentrations that would inhibit HIV. Three AMPs were also tested for their ability to inhibit growth of Neisseria lactamica, a close relative of the sexually transmissible Neisseria gonorrhoeae. Neisseria lactamica was significantly more sensitive to the AMPs than the lactobacilli. Thus, several candidate AMPs have the capacity to inhibit HIV and possible N. gonorrhoeae transmission at concentrations that are significantly less harmful to the resident lactobacilli. Full article
(This article belongs to the Special Issue Development of Antimicrobial Peptides from Amphibian)
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14 pages, 2759 KiB  
Article
Figainin 1, a Novel Amphibian Skin Peptide with Antimicrobial and Antiproliferative Properties
by Carlos José Correia Santana, Ana Carolina Martins Magalhães, Agenor C. M. dos Santos Júnior, Carlos André Ornelas Ricart, Beatriz D. Lima, Alice da Cunha Morales Álvares, Sonia Maria de Freitas, Osmindo Rodrigues Pires, Jr., Wagner Fontes and Mariana S. Castro
Antibiotics 2020, 9(9), 625; https://doi.org/10.3390/antibiotics9090625 - 21 Sep 2020
Cited by 16 | Viewed by 3370
Abstract
Amphibian skin secretions are abundant in bioactive compounds, especially antimicrobial peptides. These molecules are generally cationic and rich in hydrophobic amino acids, have an amphipathic structure and adopt an α-helical conformation when in contact with microorganisms membranes. In this work, we purified and [...] Read more.
Amphibian skin secretions are abundant in bioactive compounds, especially antimicrobial peptides. These molecules are generally cationic and rich in hydrophobic amino acids, have an amphipathic structure and adopt an α-helical conformation when in contact with microorganisms membranes. In this work, we purified and characterized Figainin 1, a novel antimicrobial and antiproliferative peptide from the cutaneous secretion of the frog Boana raniceps. Figainin 1 is a cationic peptide with eighteen amino acid residues—rich in leucine and isoleucine, with an amidated C-terminus—and adopts an α-helical conformation in the presence of trifluoroethanol (TFE). It displayed activity against Gram-negative and especially Gram-positive bacteria, with MIC values ranging from 2 to 16 µM, and showed an IC50 value of 15.9 µM against epimastigote forms of T. cruzi; however, Figanin 1 did not show activity against Candida species. This peptide also showed cytolytic effects against human erythrocytes with an HC50 of 10 µM, in addition to antiproliferative activity against cancer cells and murine fibroblasts, with IC50 values ranging from 10.5 to 13.7 µM. Despite its adverse effects on noncancerous cells, Figainin 1 exhibits interesting properties for the development of new anticancer agents and anti-infective drugs against pathogenic microorganisms. Full article
(This article belongs to the Special Issue Development of Antimicrobial Peptides from Amphibian)
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14 pages, 1434 KiB  
Article
Activity of Temporin A and Short Lipopeptides Combined with Gentamicin against Biofilm Formed by Staphylococcus aureus and Pseudomonas aeruginosa
by Malgorzata Anna Paduszynska, Katarzyna Ewa Greber, Wojciech Paduszynski, Wieslaw Sawicki and Wojciech Kamysz
Antibiotics 2020, 9(9), 566; https://doi.org/10.3390/antibiotics9090566 - 2 Sep 2020
Cited by 16 | Viewed by 2798
Abstract
The formation of biofilms on biomaterials causes biofilm-associated infections. Available treatments often fail to fight the microorganisms in the biofilm, creating serious risks for patient well-being and life. Due to their significant antibiofilm activities, antimicrobial peptides are being intensively investigated in this regard. [...] Read more.
The formation of biofilms on biomaterials causes biofilm-associated infections. Available treatments often fail to fight the microorganisms in the biofilm, creating serious risks for patient well-being and life. Due to their significant antibiofilm activities, antimicrobial peptides are being intensively investigated in this regard. A promising approach is a combination therapy that aims to increase the efficacy and broaden the spectrum of antibiotics. The main goal of this study was to evaluate the antimicrobial efficacy of temporin A and the short lipopeptides (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2 in combination with gentamicin against biofilm formed by Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA). Peptides were synthesized with solid-phase temperature-assisted synthesis methodology. The minimum inhibitory concentrations (MICs), fractional inhibitory concentrations (FICs), minimum biofilm eradication concentrations (MBECs), and the influence of combinations of compounds with gentamicin on bacterial biofilm were determined for reference strains of SA (ATCC 25923) and PA (ATCC 9027). The peptides exhibited significant potential to enhance the antibacterial activity of gentamicin against SA biofilm, but there was no synergy in activity against planktonic cells. The antibiotic applied alone demonstrated strong activity against planktonic cells and poor effectiveness against SA biofilm. Biofilm formed by PA was much more sensitive to gentamicin, but some positive influences of supplementation with peptides were noticed. The results of the performed experiments suggest that the potential application of peptides as adjuvant agents in the treatment of biofilm-associated infections should be studied further. Full article
(This article belongs to the Special Issue Development of Antimicrobial Peptides from Amphibian)
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26 pages, 1917 KiB  
Article
Bioinformatic Analysis of 1000 Amphibian Antimicrobial Peptides Uncovers Multiple Length-Dependent Correlations for Peptide Design and Prediction
by Guangshun Wang
Antibiotics 2020, 9(8), 491; https://doi.org/10.3390/antibiotics9080491 - 7 Aug 2020
Cited by 36 | Viewed by 5606
Abstract
Amphibians are widely distributed on different continents, except for the polar regions. They are important sources for the isolation, purification and characterization of natural compounds, including peptides with various functions. Innate immune antimicrobial peptides (AMPs) play a critical role in warding off invading [...] Read more.
Amphibians are widely distributed on different continents, except for the polar regions. They are important sources for the isolation, purification and characterization of natural compounds, including peptides with various functions. Innate immune antimicrobial peptides (AMPs) play a critical role in warding off invading pathogens, such as bacteria, fungi, parasites, and viruses. They may also have other biological functions such as endotoxin neutralization, chemotaxis, anti-inflammation, and wound healing. This article documents a bioinformatic analysis of over 1000 amphibian antimicrobial peptides registered in the Antimicrobial Peptide Database (APD) in the past 18 years. These anuran peptides were discovered in Africa, Asia, Australia, Europe, and America from 1985 to 2019. Genomic and peptidomic studies accelerated the discovery pace and underscored the necessity in establishing criteria for peptide entry into the APD. A total of 99.9% of the anuran antimicrobial peptides are less than 50 amino acids with an average length of 24 and a net charge of +2.5. Interestingly, the various amphibian peptide families (e.g., temporins, brevinins, esculentins) can be connected through multiple length-dependent relationships. With an increase in length, peptide net charge increases, while the hydrophobic content decreases. In addition, glycine, leucine, lysine, and proline all show linear correlations with peptide length. These correlations improve our understanding of amphibian peptides and may be useful for prediction and design of new linear peptides with potential applications in treating infectious diseases, cancer and diabetes. Full article
(This article belongs to the Special Issue Development of Antimicrobial Peptides from Amphibian)
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19 pages, 5068 KiB  
Article
Antimicrobial Property and Mode of Action of the Skin Peptides of the Sado Wrinkled Frog, Glandirana susurra, against Animal and Plant Pathogens
by Daisuke Ogawa, Manami Suzuki, Yuriko Inamura, Kaito Saito, Itaru Hasunuma, Tetsuya Kobayashi, Sakae Kikuyama and Shawichi Iwamuro
Antibiotics 2020, 9(8), 457; https://doi.org/10.3390/antibiotics9080457 - 29 Jul 2020
Cited by 3 | Viewed by 3109
Abstract
The Sado wrinkled frog Glandirana susurra has recently been classified as a new frog species endemic to Sado Island, Japan. In this study, we cloned 12 cDNAs encoding the biosynthetic precursors for brevinin-2SSa–2SSd, esculentin-2SSa, ranatuerin-2SSa, brevinin-1SSa–1SSd, granuliberin-SSa, and bradykinin-SSa from the skin of [...] Read more.
The Sado wrinkled frog Glandirana susurra has recently been classified as a new frog species endemic to Sado Island, Japan. In this study, we cloned 12 cDNAs encoding the biosynthetic precursors for brevinin-2SSa–2SSd, esculentin-2SSa, ranatuerin-2SSa, brevinin-1SSa–1SSd, granuliberin-SSa, and bradykinin-SSa from the skin of G. susurra. Among these antimicrobial peptides, we focused on brevinin-2SSb, ranatuerin-2SSa, and granuliberin-SSa, using their synthetic replicates to examine their activities against different reference strains of pathogenic microorganisms that infect animals and plants. In broth microdilution assays, brevinin-2SSb displayed antimicrobial activities against animal pathogens Escherichia coli, Salmonella enterica, Pseudomonas aeruginosa, and Candida albicans and plant pathogens Xanthomonas oryzae pv. oryzae, Clavibacter michiganensis subsp. michiganensis, and Pyricularia oryzae. Ranatuerin-2SSa and granuliberin-SSa were active against C. albicans and C. michiganensis subsp. michiganensis, and granuliberin-SSa also was active against the other plant pathogenic microbes. Scanning electron microscopic observations demonstrated that brevinin-2SSb, ranatuerin-2SSa, and granuliberin-SSa induced morphological abnormalities on the cell surface in a wide range of the reference pathogens. To assess the bacterial-endotoxin-binding ability of the peptides, we developed an enzyme-linked endotoxin-binding assay system and demonstrated that brevinin-2SSb and ranatuerin-2SSa both exhibited high affinity to lipopolysaccharide and moderate affinity to lipoteichoic acid. Full article
(This article belongs to the Special Issue Development of Antimicrobial Peptides from Amphibian)
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13 pages, 887 KiB  
Article
Frog Skin-Derived Peptides Against Corynebacterium jeikeium: Correlation between Antibacterial and Cytotoxic Activities
by Bruno Casciaro, Maria Rosa Loffredo, Floriana Cappiello, Walter Verrusio, Vito Domenico Corleto and Maria Luisa Mangoni
Antibiotics 2020, 9(8), 448; https://doi.org/10.3390/antibiotics9080448 - 26 Jul 2020
Cited by 11 | Viewed by 3317
Abstract
Corynebacterium jeikeium is a commensal bacterium that colonizes human skin, and it is part of the normal bacterial flora. In non-risk subjects, it can be the cause of bad body smell due to the generation of volatile odorous metabolites, especially in the wet [...] Read more.
Corynebacterium jeikeium is a commensal bacterium that colonizes human skin, and it is part of the normal bacterial flora. In non-risk subjects, it can be the cause of bad body smell due to the generation of volatile odorous metabolites, especially in the wet parts of the body that this bacterium often colonizes (i.e., groin and axillary regions). Importantly, in the last few decades, there have been increasing cases of serious infections provoked by this bacterium, especially in immunocompromised or hospitalized patients who have undergone installation of prostheses or catheters. The ease in developing resistance to commonly-used antibiotics (i.e., glycopeptides) has made the search for new antimicrobial compounds of clinical importance. Here, for the first time, we characterize the antimicrobial activity of some selected frog skin-derived antimicrobial peptides (AMPs) against C. jeikeium by determining their minimum inhibitory and bactericidal concentrations (MIC and MBC) by a microdilution method. The results highlight esculentin-1b(1-18) [Esc(1-18)] and esculentin-1a(1-21) [Esc(1-21)] as the most active AMPs with MIC and MBC of 4–8 and 0.125–0.25 µM, respectively, along with a non-toxic profile after a short- and long-term (40 min and 24 h) treatment of mammalian cells. Overall, these findings indicate the high potentiality of Esc(1-18) and Esc(1-21) as (i) alternative antimicrobials against C. jeikeium infections and/or as (ii) additives in cosmetic products (creams, deodorants) to reduce the production of bad body odor. Full article
(This article belongs to the Special Issue Development of Antimicrobial Peptides from Amphibian)
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14 pages, 2473 KiB  
Article
Identification and Rational Design of a Novel Antibacterial Peptide Dermaseptin-AC from the Skin Secretion of the Red-Eyed Tree Frog Agalychnis callidryas
by Zijian Gong, Xinjie Pei, Shen Ren, Xiaoling Chen, Lei Wang, Chengbang Ma, Xinping Xi, Tianbao Chen, Chris Shaw and Mei Zhou
Antibiotics 2020, 9(5), 243; https://doi.org/10.3390/antibiotics9050243 - 10 May 2020
Cited by 14 | Viewed by 3830
Abstract
Antibiotic resistance represents a tremendous contemporary clinical challenge. Given this challenge, antimicrobial peptides (AMPs) are regarded as one of the most promising new options for next-generation lead antibiotics. Here, we describe the antibacterial activities of a cationic peptide named DRP-AC4, obtained from frog [...] Read more.
Antibiotic resistance represents a tremendous contemporary clinical challenge. Given this challenge, antimicrobial peptides (AMPs) are regarded as one of the most promising new options for next-generation lead antibiotics. Here, we describe the antibacterial activities of a cationic peptide named DRP-AC4, obtained from frog skin secretion using shotgun cloning. Two modified peptides were derived by substituting the sequence of amino acids to complete the hydrophobic face (DRP-AC4b) and increase net charge (DRP-AC4a), respectively. The activity and cytotoxicity of these two peptides were compared. DRP-AC4a displayed significantly increased potency against bacteria compared to the natural peptide. It should be noted, however, that both analogue peptides demonstrated higher lytic ability than the natural peptide against the membranes of mammalian erythrocytes. At the same time, all three peptides displayed lower hemolytic activity compared to their antibacterial activity. Here, we demonstrate that AMPs have more complex activity mechanisms and faster bactericidal rates than traditional antibiotics, which may be one of the reasons why bacteria do not develop resistance to them. These discoveries provide interesting insights into the discovery and development of novel drugs from natural sources. Full article
(This article belongs to the Special Issue Development of Antimicrobial Peptides from Amphibian)
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11 pages, 1577 KiB  
Article
Brevinin-2GHk from Sylvirana guentheri and the Design of Truncated Analogs Exhibiting the Enhancement of Antimicrobial Activity
by Guanzhu Chen, Yuxi Miao, Chengbang Ma, Mei Zhou, Zhanzhong Shi, Xiaoling Chen, James F. Burrows, Xinping Xi, Tianbao Chen and Lei Wang
Antibiotics 2020, 9(2), 85; https://doi.org/10.3390/antibiotics9020085 - 14 Feb 2020
Cited by 15 | Viewed by 3462
Abstract
Brevinins are an important antimicrobial peptide (AMP) family discovered in the skin secretions of Ranidae frogs. The members demonstrate a typical C-terminal ranabox, as well as a diverse range of other structural characteristics. In this study, we identified a novel brevinin-2 peptide from [...] Read more.
Brevinins are an important antimicrobial peptide (AMP) family discovered in the skin secretions of Ranidae frogs. The members demonstrate a typical C-terminal ranabox, as well as a diverse range of other structural characteristics. In this study, we identified a novel brevinin-2 peptide from the skin secretion of Sylvirana guentheri, via cloning transcripts, and identifying the expressed mature peptide, in the skin secretion. The confirmed amino acid sequence of the mature peptide was designated brevinin-2GHk (BR2GK). Moreover, as a previous study had demonstrated that the N-terminus of brevinin-2 is responsible for exerting antimicrobial activity, we also designed a series of truncated derivatives of BR2GK. The results show that the truncated derivatives exhibit significantly improved antimicrobial activity and cytotoxicity compared to the parent peptide, except a Pro14 substituted analog. The circular dichroism (CD) analysis of this analog revealed that it did not fold into a helical conformation in the presence of either lipopolysaccharides (LPS) or TFE, indicating that position 14 is involved in the formation of the α-helix. Furthermore, three more analogs with the substitutions of Ala, Lys and Arg at the position 14, respectively, revealed the influence on the membrane disruption potency on bacteria and mammalian cells by the structural changes at this position. Overall, the N-terminal 25-mer truncates demonstrated the potent antimicrobial activity with low cytotoxicity. Full article
(This article belongs to the Special Issue Development of Antimicrobial Peptides from Amphibian)
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