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In Vitro and In Vivo Studies of Natural Antimicrobial Peptides...
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In Vitro and In Vivo Studies of Natural Antimicrobial Peptides as Promising Therapeutic Agents

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 12330

Special Issue Editors

Dr. Sergey V. Balandin

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Guest Editor
Shemyakin Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
Interests: antibiotics; antimicrobial peptides; bacteriocins; lantibiotics; pediocin-like peptides; molecular evolution; protein expression and purification; synthetic biology
Special Issues, Collections and Topics in MDPI journals
Dr. Ekaterina I. Finkina

E-Mail Website
Guest Editor
M.M. Shemyakin & Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
Interests: plant innate immunity; plant pathogenesis related proteins (PR-proteins); lipid transfer proteins (LTPs); defensins; Bet v 1 homologues; lipid binding; antimicrobial activity; membrane permeability; recombinant expression of proteins; plant allergens; allergy; sensitization
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to introduce a Special Issue of MDPI Pharmaceutics dedicated to ribosomally synthesized antimicrobial peptides (AMPs) as scaffolds for creating new promising therapeutic agents. AMPs are a diverse group of small molecules with the ability to kill or inhibit the growth of a wide range of microorganisms, including bacteria, fungi, and viruses. AMPs are essential components of innate immunity in multicellular organisms and factors that allow unicellular organisms to compete with other species for nutrients. In addition to their direct antimicrobial action, they can act as regulatory (signaling) molecules that mobilize the cells of the host organism or produce a microbial population to overcome stress conditions.

Most AMPs have a membrane-targeting mechanism of action, which is often complemented by an inhibitory effect against specific biochemical subsystems of the target cells (bacterial ribosomes, peptidoglycan or lipopolysaccharide biosynthetic paths, etc.), which makes it difficult for micro-organisms to evolve stable resistance against them. The difference in the mechanisms of action with conventional antibiotics allows synergistic effects to be achieved when they are used in combination. Currently, the pharmaceutical use of AMPs is limited to probiotic formulations that contain bacteriocin-producing strains exhibiting antagonism to intestinal pathogens. Nevertheless, extensive work is underway to evaluate the therapeutic potential of AMP preparations against systemic infections and for wound healing. The main problems of this approach are the high production cost of recombinant and synthetic AMPs, as well as their susceptibility to proteolytic degradation under physiological conditions. To date, several dozens of AMP-based drugs have undergone preclinical and clinical trials.

We hope that this Special Issue will serve as a communication platform for researchers in the field of AMPs. We invite you to send primary research manuscripts and review articles concerning the structure of AMPs, biological activity assays on cultures of pro- and eukaryotic cells, in vivo studies in animal models of infection, delivery systems, mechanisms of resistance formation, screening technologies, and rational design of therapeutically valuable analogs of natural peptides.

Dr. Sergey V. Balandin
Dr. Ekaterina I. Finkina
Guest Editors

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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 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

  • antibiotics
  • antimicrobial peptides (AMPs)
  • bacteriocins
  • preclinical and clinical trials
  • drug resistance
  • host defense peptides
  • mechanisms of antimicrobial activity
  • peptide therapeutics
  • structure–activity relationships

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Published Papers (5 papers)

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Research

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10 pages, 2299 KiB  
Article
Discovery of Novel Thanatin-like Antimicrobial Peptides from Bean Bug Riptortus pedestris
by Pavel V. Panteleev, Julia S. Teplovodskaya, Anastasia D. Utkina, Anastasia A. Smolina, Roman N. Kruglikov, Victoria N. Safronova, Ilia A. Bolosov, Olga V. Korobova, Alexander I. Borzilov and Tatiana V. Ovchinnikova
Pharmaceutics 2024, 16(11), 1453; https://doi.org/10.3390/pharmaceutics16111453 - 14 Nov 2024
Viewed by 373
Abstract
Background: Endogenous antimicrobial peptides (AMPs) are evolutionarily ancient molecular factors of innate immunity that play a key role in host defense. The study of the diversity of animal defense peptides has important applications in the context of the growing global antimicrobial resistance. Methods: [...] Read more.
Background: Endogenous antimicrobial peptides (AMPs) are evolutionarily ancient molecular factors of innate immunity that play a key role in host defense. The study of the diversity of animal defense peptides has important applications in the context of the growing global antimicrobial resistance. Methods: In this study using a transcriptome mining approach, we found three novel thanatin-like β-hairpin AMPs in the bean bug Riptortus pedestris, named Rip-2, Rip-3, and Rip-4. The peptides were expressed in the bacterial system, and their antimicrobial activities were evaluated both in vitro and in vivo. Results: Homologs of the discovered AMPs are widely distributed among different members of the infraorder Pentatomomorpha. Rip-2 was shown to have the most similar structure and LptA-targeting mechanism of action to those of thanatin, but the former peptides demonstrated a higher activity against key Gram-negative ESKAPE pathogens and also displayed a significant efficacy in a lethal model of septicemia caused by E. coli in mice at daily doses greater than 5 mg/kg. In contrast, Rip-3 and Rip-4 peptides caused bacterial membrane damage, did not induce bacterial resistance, and exhibited a strong selectivity against Bacillus and Mycobacterium spp. Conclusions: This study extends the knowledge of the structure and functions of insect host defense AMPs. Each of the novel β-hairpin peptides has a potential to be a template for the development of selective antibiotic drugs. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Studies of Natural Antimicrobial Peptides as Promising Therapeutic Agents)
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13 pages, 2456 KiB  
Article
Identification, Synthesis, and In Vitro Activities of Antimicrobial Peptide from African Catfish against the Extended-Spectrum Beta-Lactamase (ESBL)-Producing Escherichia coli
by Hedmon Okella, Steven Odongo, Didier Vertommen and Emmanuel Okello
Pharmaceutics 2024, 16(7), 850; https://doi.org/10.3390/pharmaceutics16070850 - 22 Jun 2024
Viewed by 1777
Abstract
The global surge in multi-drug resistant bacteria, including extended-spectrum β-lactamase (ESBL)-producing Escherichia coli has led to a growing need for new antibacterial compounds. Despite being promising, the potential of fish-derived antimicrobial peptides (AMPs) in combating ESBL-producing E. coli is largely unexplored. In this [...] Read more.
The global surge in multi-drug resistant bacteria, including extended-spectrum β-lactamase (ESBL)-producing Escherichia coli has led to a growing need for new antibacterial compounds. Despite being promising, the potential of fish-derived antimicrobial peptides (AMPs) in combating ESBL-producing E. coli is largely unexplored. In this study, native African catfish antimicrobial peptides (NACAPs) were extracted from the skin mucus of farmed African catfish, Clarias gariepinus, using a combination of 10% acetic acid solvent hydrolysis, 5 kDa ultrafiltration, and C18 hydrophobic interaction chromatography. Peptides were then sequenced using Orbitrap Fusion Lumos Tribrid Mass Spectrometry. The identified peptides were screened for potential antibacterial activity using Random Forest and AdaBoost machine learning algorithms. The most promising peptide was chemically synthesized and evaluated in vitro for safety on rabbit red blood cells and activity against ESBL-producing E. coli (ATCC 35218) utilizing spot-on-lawn and broth dilution methods. Eight peptides ranging from 13 to 22 amino acids with molecular weights between 968.42 and 2434.11 Da were identified. Peptide NACAP-II was non-hemolytic to rabbit erythrocytes (p > 0.05) with a zone of inhibition (ZOI) of 22.7 ± 0.9 mm and a minimum inhibitory concentration (MIC) of 91.3 ± 1.2 μg/mL. The peptide is thus a candidate antibacterial compound with enormous potential applications in the pharmaceutical industry. However, further studies are still required to establish an upscale production strategy and optimize its activity and safety in vivo. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Studies of Natural Antimicrobial Peptides as Promising Therapeutic Agents)
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13 pages, 1638 KiB  
Article
Antiviral Effect of Antimicrobial Peptoid TM9 and Murine Model of Respiratory Coronavirus Infection
by Maxim Lebedev, Aaron B. Benjamin, Sathish Kumar, Natalia Molchanova, Jennifer S. Lin, Kent J. Koster, Julian L. Leibowitz, Annelise E. Barron and Jeffrey D. Cirillo
Pharmaceutics 2024, 16(4), 464; https://doi.org/10.3390/pharmaceutics16040464 - 27 Mar 2024
Viewed by 1706
Abstract
New antiviral agents are essential to improving treatment and control of SARS-CoV-2 infections that can lead to the disease COVID-19. Antimicrobial peptoids are sequence-specific oligo-N-substituted glycine peptidomimetics that emulate the structure and function of natural antimicrobial peptides but are resistant to [...] Read more.
New antiviral agents are essential to improving treatment and control of SARS-CoV-2 infections that can lead to the disease COVID-19. Antimicrobial peptoids are sequence-specific oligo-N-substituted glycine peptidomimetics that emulate the structure and function of natural antimicrobial peptides but are resistant to proteases. We demonstrate antiviral activity of a new peptoid (TM9) against the coronavirus, murine hepatitis virus (MHV), as a closely related model for the structure and antiviral susceptibility profile of SARS-CoV-2. This peptoid mimics the human cathelicidin LL-37, which has also been shown to have antimicrobial and antiviral activity. In this study, TM9 was effective against three murine coronavirus strains, demonstrating that the therapeutic window is large enough to allow the use of TM9 for treatment. All three isolates of MHV generated infection in mice after 15 min of exposure by aerosol using the Madison aerosol chamber, and all three viral strains could be isolated from the lungs throughout the 5-day observation period post-infection, with the peak titers on day 2. MHV-A59 and MHV-A59-GFP were also isolated from the liver, heart, spleen, olfactory bulbs, and brain. These data demonstrate that MHV serves as a valuable natural murine model of coronavirus pathogenesis in multiple organs, including the brain. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Studies of Natural Antimicrobial Peptides as Promising Therapeutic Agents)
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15 pages, 2909 KiB  
Article
Design of Protegrin-1 Analogs with Improved Antibacterial Selectivity
by Ilia A. Bolosov, Pavel V. Panteleev, Sergei V. Sychev, Veronika A. Khokhlova, Victoria N. Safronova, Ilia Yu. Toropygin, Tatiana I. Kombarova, Olga V. Korobova, Eugenia S. Pereskokova, Alexander I. Borzilov, Tatiana V. Ovchinnikova and Sergey V. Balandin
Pharmaceutics 2023, 15(8), 2047; https://doi.org/10.3390/pharmaceutics15082047 - 30 Jul 2023
Cited by 5 | Viewed by 1772
Abstract
Protegrin-1 (PG-1) is a cationic β-hairpin pore-forming antimicrobial peptide having a membranolytic mechanism of action. It possesses in vitro a potent antimicrobial activity against a panel of clinically relevant MDR ESKAPE pathogens. However, its extremely high hemolytic activity and cytotoxicity toward mammalian cells [...] Read more.
Protegrin-1 (PG-1) is a cationic β-hairpin pore-forming antimicrobial peptide having a membranolytic mechanism of action. It possesses in vitro a potent antimicrobial activity against a panel of clinically relevant MDR ESKAPE pathogens. However, its extremely high hemolytic activity and cytotoxicity toward mammalian cells prevent the further development of the protegrin-based antibiotic for systemic administration. In this study, we rationally modulated the PG-1 charge and hydrophobicity by substituting selected residues in the central β-sheet region of PG-1 to design its analogs, which retain a high antimicrobial activity but have a reduced toxicity toward mammalian cells. In this work, eight PG-1 analogs with single amino acid substitutions and five analogs with double substitutions were obtained. These analogs were produced as thioredoxin fusions in Escherichia coli. It was shown that a significant reduction in hemolytic activity without any loss of antimicrobial activity could be achieved by a single amino acid substitution, V16R in the C-terminal β-strand, which is responsible for the PG-1 oligomerization. As the result, a selective analog with a ≥30-fold improved therapeutic index was obtained. FTIR spectroscopy analysis of analog, [V16R], revealed that the peptide is unable to form oligomeric structures in a membrane-mimicking environment, in contrast to wild-type PG-1. Analog [V16R] showed a reasonable efficacy in septicemia infection mice model as a systemic antibiotic and could be considered as a promising lead for further drug design. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Studies of Natural Antimicrobial Peptides as Promising Therapeutic Agents)
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Review

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44 pages, 1993 KiB  
Review
Bacillus licheniformis: A Producer of Antimicrobial Substances, including Antimycobacterials, Which Are Feasible for Medical Applications
by Margarita O. Shleeva, Daria A. Kondratieva and Arseny S. Kaprelyants
Pharmaceutics 2023, 15(7), 1893; https://doi.org/10.3390/pharmaceutics15071893 - 5 Jul 2023
Cited by 11 | Viewed by 5707
Abstract
Bacillus licheniformis produces several classes of antimicrobial substances, including bacteriocins, which are peptides or proteins with different structural composition and molecular mass: ribosomally synthesized by bacteria (1.4–20 kDa), non-ribosomally synthesized peptides and cyclic lipopeptides (0.8–42 kDa) and exopolysaccharides (>1000 kDa). Different bacteriocins act [...] Read more.
Bacillus licheniformis produces several classes of antimicrobial substances, including bacteriocins, which are peptides or proteins with different structural composition and molecular mass: ribosomally synthesized by bacteria (1.4–20 kDa), non-ribosomally synthesized peptides and cyclic lipopeptides (0.8–42 kDa) and exopolysaccharides (>1000 kDa). Different bacteriocins act against Gram-positive or Gram-negative bacteria, fungal pathogens and amoeba cells. The main mechanisms of bacteriocin lytic activity include interaction of peptides with membranes of target cells resulting in structural alterations, pore-forming, and inhibition of cell wall biosynthesis. DNase and RNase activity for some bacteriocines are also postulated. Non-ribosomal peptides are synthesized by special non-ribosomal multimodular peptide synthetases and contain unnatural amino acids or fatty acids. Their harmful effect is due to their ability to form pores in biological membranes, destabilize lipid packaging, and disrupt the peptidoglycan layer. Lipopeptides, as biosurfactants, are able to destroy bacterial biofilms. Secreted polysaccharides are high molecular weight compounds, composed of repeated units of sugar moieties attached to a carrier lipid. Their antagonistic action was revealed in relation to bacteria, viruses, and fungi. Exopolysaccharides also inhibit the formation of biofilms by pathogenic bacteria and prevent their colonization on various surfaces. However, mechanism of the harmful effect for many secreted antibacterial substances remains unknown. The antimicrobial activity for most substances has been studied in vitro only, but some substances have been characterized in vivo and they have found practical applications in medicine and veterinary. The cyclic lipopeptides that have surfactant properties are used in some industries. In this review, special attention is paid to the antimycobacterials produced by B. licheniformis as a possible approach to combat multidrug-resistant and latent tuberculosis. In particular, licheniformins and bacitracins have shown strong antimycobacterial activity. However, the medical application of some antibacterials with promising in vitro antimycobacterial activity has been limited by their toxicity to animals and humans. As such, similar to the enhancement in the antimycobacterial activity of natural bacteriocins achieved using genetic engineering, the reduction in toxicity using the same approach appears feasible. The unique capability of B. licheniformis to synthesize and produce a range of different antibacterial compounds means that this organism can act as a natural universal vehicle for antibiotic substances in the form of probiotic cultures and strains to combat various types of pathogens, including mycobacteria. Full article
(This article belongs to the Special Issue In Vitro and In Vivo Studies of Natural Antimicrobial Peptides as Promising Therapeutic Agents)
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