Antimicrobial Peptides and Proteins: A Potential Approach to Treat and Combat Antimicrobial Resistance

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Biopharmaceuticals".

Deadline for manuscript submissions: closed (22 April 2024) | Viewed by 10641

Special Issue Editors


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Guest Editor
Department of Biology, University of Naples Federico II, Naples, Italy
Interests: antimicrobial peptides and proteins; host defence peptides; drug discovery; LPS scavengers; immune modulation; antibiofilm agents; toxins

E-Mail Website
Guest Editor
Department of Biology, University of Naples Federico II, Naples, Italy
Interests: antimicrobial peptides; peptide fluorescent labeling; antimicrobial synergy; prevention of the biofilm formation and eradication; peptide-LPS interactions

Special Issue Information

Dear Colleagues,

According to the World Health Organization (WHO), antimicrobial resistance (AMR) occurs when bacteria, viruses, fungi, and parasites change and no longer respond to drugs, making infections harder to treat. In 1945, Fleming had already warned about the dangers of misusing penicillin, and almost 80 years later, the problem of AMR is more relevant than ever. To date, fighting AMR requires the development of innovative vaccines, diagnostics, and, above all, therapeutics that are able to escape the strategies implemented by microorganisms to resist antibiotics. Antimicrobial peptides and proteins (AMPs), also known as Host defense peptides and proteins (HDPs), are the most promising candidates for alternative therapeutics to combat AMR since they are ancient components of the innate immune system. They are present in many organisms and are endowed with unique structural properties that allow not only the permeation and disruption of the target membranes but also the stimulation of the immune response. AMPs/HDPs have a wide range of inhibitory effects against bacteria, fungi, parasites, and viruses but have the advantages of limiting the induction and development of resistance mechanisms. Interestingly, during the last few years, research into new natural antimicrobial agents has been flanked by the rational design of new synthetic molecules inspired by natural agents and by the identification of novel bioactive sequences hidden in larger proteins, called cryptides.

We therefore invite academic investigators working in these fields to submit original research articles or reviews describing and discussing the most recent advancements and developments in basic science and biomedical applications.

Potential topics include but are not limited to:

  • The discovery and design of novel AMPs/HDPs;
  • Analysis of the structure and function of AMPs/HDPs;
  • Modes of action of AMPs/HDPs and their effects on microbes, eukaryotic cells, and animal model systems;
  • Characterization of AMPs/HDPs interaction with membranes;
  • Peptidomimetics;
  • Characterization of modified peptides;
  • Identification of bioactive cryptides.

Dr. Andrea Bosso
Dr. Valeria Cafaro
Guest Editors

Manuscript Submission Information

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Keywords

  • antimicrobial peptides
  • host defense peptides
  • cryptides
  • antimicrobial peptidomimetics
  • endotoxin neutralization
  • antibiofilm activity
  • wound healing
  • antibiotic resistance
  • membrane-disrupting peptides
  • molecular targets of AMPs
  • medical device contamination

Published Papers (7 papers)

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Research

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13 pages, 1233 KiB  
Article
Efficiency of NZ2114 on Superficial Pyoderma Infected with Staphylococcus pseudintermedius
by Na Yang, Yan Huang, Yuanyuan Li, Da Teng, Ruoyu Mao, Ya Hao, Lingyun Wei and Jianhua Wang
Pharmaceuticals 2024, 17(3), 277; https://doi.org/10.3390/ph17030277 - 22 Feb 2024
Cited by 1 | Viewed by 777
Abstract
Staphylococcus pseudintermedius (S. pseudintermedius) is the main pathogen causing pyoderma of canines. With the emergence of drug-resistant bacteria, traditional antibiotic treatments are limited. As a potential antibacterial agent, NZ2114 was effective against S. pseudintermedius, including drug-resistant strains. Its bactericidal efficacy [...] Read more.
Staphylococcus pseudintermedius (S. pseudintermedius) is the main pathogen causing pyoderma of canines. With the emergence of drug-resistant bacteria, traditional antibiotic treatments are limited. As a potential antibacterial agent, NZ2114 was effective against S. pseudintermedius, including drug-resistant strains. Its bactericidal efficacy was superior to mupiroxacin, ofloxacin and lincomycin. To facilitate the transcutaneous delivery of NZ2114 for the treatment of superficial pyoderma, chemical permeation enhancers were added since water-soluble NZ2114 does not easily penetrate the skin lipid layer. Two different NZ2114 sprays were prepared by combining 1% Azone + 10% propylene glycol (PG) or 5% N-methylpyrrolidone (NMP) + 10% PG with NZ2114 after screening. The cumulative permeability of NZ2114 sprays were 244.149 and 405.245 μg/cm2 at 24 h with an in vitro percutaneous assay of mice skin, which showed a 244% and 405% increase in skin permeability than NZ2114, respectively. In addition, the efficacy of NZ2114 sprays in reducing skin bacteria colonisation was demonstrated in a mouse model of superficial pyoderma (24 mice, 3 mice/group) induced by S. pseudintermedius, and the 5% NMP + 10% PG + NZ2114 group had the best therapeutic effect compared to the other groups. This preparation did not cause any skin irritation, laying the foundation for the development of an effective and non-toxic topical product. Full article
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16 pages, 5415 KiB  
Article
Effects of Escherichia coli LPS Structure on Antibacterial and Anti-Endotoxin Activities of Host Defense Peptides
by Ali Javed, Melanie D. Balhuizen, Arianne Pannekoek, Floris J. Bikker, Dani A. C. Heesterbeek, Henk P. Haagsman, Femke Broere, Markus Weingarth and Edwin J. A. Veldhuizen
Pharmaceuticals 2023, 16(10), 1485; https://doi.org/10.3390/ph16101485 - 18 Oct 2023
Viewed by 1283
Abstract
The binding of Host Defense Peptides (HDPs) to the endotoxin of Gram-negative bacteria has important unsolved aspects. For most HDPs, it is unclear if binding is part of the antibacterial mechanism or whether LPS actually provides a protective layer against HDP killing. In [...] Read more.
The binding of Host Defense Peptides (HDPs) to the endotoxin of Gram-negative bacteria has important unsolved aspects. For most HDPs, it is unclear if binding is part of the antibacterial mechanism or whether LPS actually provides a protective layer against HDP killing. In addition, HDP binding to LPS can block the subsequent TLR4-mediated activation of the immune system. This dual activity is important, considering that HDPs are thought of as an alternative to conventional antibiotics, which do not provide this dual activity. In this study, we systematically determine, for the first time, the influence of the O-antigen and Lipid A composition on both the antibacterial and anti-endotoxin activity of four HDPs (CATH-2, PR-39, PMAP-23, and PMAP36). The presence of the O-antigen did not affect the antibacterial activity of any of the tested HDPs. Similarly, modification of the lipid A phosphate (MCR-1 phenotype) also did not affect the activity of the HDPs. Furthermore, assessment of inner and outer membrane damage revealed that CATH-2 and PMAP-36 are profoundly membrane-active and disrupt the inner and outer membrane of Escherichia coli simultaneously, suggesting that crossing the outer membrane is the rate-limiting step in the bactericidal activity of these HDPs but is independent of the presence of an O-antigen. In contrast to killing, larger differences were observed for the anti-endotoxin properties of HDPs. CATH-2 and PMAP-36 were much stronger at suppressing LPS-induced activation of macrophages compared to PR-39 and PMAP-23. In addition, the presence of only one phosphate group in the lipid A moiety reduced the immunomodulating activity of these HDPs. Overall, the data strongly suggest that LPS composition has little effect on bacterial killing but that Lipid A modification can affect the immunomodulatory role of HDPs. This dual activity should be considered when HDPs are considered for application purposes in the treatment of infectious diseases. Full article
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26 pages, 4281 KiB  
Article
The Antimicrobial, Antibiofilm and Anti-Inflammatory Activities of P13#1, a Cathelicidin-like Achiral Peptoid
by Valeria Cafaro, Andrea Bosso, Ilaria Di Nardo, Assunta D’Amato, Irene Izzo, Francesco De Riccardis, Marialuisa Siepi, Rosanna Culurciello, Nunzia D’Urzo, Emiliano Chiarot, Antonina Torre, Elio Pizzo, Marcello Merola and Eugenio Notomista
Pharmaceuticals 2023, 16(10), 1386; https://doi.org/10.3390/ph16101386 - 30 Sep 2023
Cited by 1 | Viewed by 1076
Abstract
Cationic antimicrobial peptides (CAMPs) are powerful molecules with antimicrobial, antibiofilm and endotoxin-scavenging activities. These properties make CAMPs very attractive drugs in the face of the rapid increase in multidrug-resistant (MDR) pathogens, but they are limited by their susceptibility to proteolytic degradation. An intriguing [...] Read more.
Cationic antimicrobial peptides (CAMPs) are powerful molecules with antimicrobial, antibiofilm and endotoxin-scavenging activities. These properties make CAMPs very attractive drugs in the face of the rapid increase in multidrug-resistant (MDR) pathogens, but they are limited by their susceptibility to proteolytic degradation. An intriguing solution to this issue could be the development of functional mimics of CAMPs with structures that enable the evasion of proteases. Peptoids (N-substituted glycine oligomers) are an important class of peptidomimetics with interesting benefits: easy synthetic access, intrinsic proteolytic stability and promising bioactivities. Here, we report the characterization of P13#1, a 13-residue peptoid specifically designed to mimic cathelicidins, the best-known and most widespread family of CAMPs. P13#1 showed all the biological activities typically associated with cathelicidins: bactericidal activity over a wide spectrum of strains, including several ESKAPE pathogens; the ability to act in combination with different classes of conventional antibiotics; antibiofilm activity against preformed biofilms of Pseudomonas aeruginosa, comparable to that of human cathelicidin LL-37; limited toxicity; and an ability to inhibit LPS-induced proinflammatory effects which is comparable to that of “the last resource” antibiotic colistin. We further studied the interaction of P13#1 with SDS, LPSs and bacterial cells by using a fluorescent version of P13#1. Finally, in a subcutaneous infection mouse model, it showed antimicrobial and anti-inflammatory activities comparable to ampicillin and gentamicin without apparent toxicity. The collected data indicate that P13#1 is an excellent candidate for the formulation of new antimicrobial therapies. Full article
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16 pages, 3467 KiB  
Article
Multifunctional Properties of BMAP-18 and Its Aliphatic Analog against Drug-Resistant Bacteria
by Ishrat Jahan, Sukumar Dinesh Kumar, Song Yub Shin, Chul Won Lee, Sung-Heui Shin and Sungtae Yang
Pharmaceuticals 2023, 16(10), 1356; https://doi.org/10.3390/ph16101356 - 25 Sep 2023
Cited by 2 | Viewed by 1084
Abstract
BMAP-18, derived from the N-terminal region of bovine myeloid antimicrobial peptide BMAP-27, demonstrates potent antimicrobial activity without cytotoxicity. This study aimed to compare the antibacterial, antibiofilm, and anti-inflammatory properties of BMAP-18, rich in aromatic phenylalanine residues, with its aliphatic analog, BMAP-18-FL. Both aromatic [...] Read more.
BMAP-18, derived from the N-terminal region of bovine myeloid antimicrobial peptide BMAP-27, demonstrates potent antimicrobial activity without cytotoxicity. This study aimed to compare the antibacterial, antibiofilm, and anti-inflammatory properties of BMAP-18, rich in aromatic phenylalanine residues, with its aliphatic analog, BMAP-18-FL. Both aromatic BMAP-18 and aliphatic BMAP-18-FL exhibited equally potent antimicrobial activities against Gram-positive and Gram-negative bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MDRPA). Mechanistic investigations employing SYTOX green uptake, DNA binding, and FACScan analysis revealed that both peptides acted by inducing membrane permeabilization and subsequent intracellular targeting. Moreover, both BMAP-18 and BMAP-18-FL effectively prevented biofilm formation and eradicated existing biofilms of MRSA and MDRPA. Notably, BMAP-18-FL displayed a superior anti-inflammatory activity compared to BMAP-18, significantly reducing the expression levels of pro-inflammatory cytokines in lipopolysaccharide-stimulated macrophages. This study emphasizes the similarities and differences in the antimicrobial, antibiofilm, and anti-inflammatory properties between aromatic BMAP-18 and aliphatic BMAP-18-FL, providing valuable insights for the development of multifunctional antimicrobial peptides against drug-resistant bacteria. Full article
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16 pages, 3604 KiB  
Article
Hylin-a1: A Host Defense Peptide with Antibacterial Potential against Staphylococcus aureus Multi-Resistant Strains
by Annalisa Chianese, Carla Zannella, Francesco Foglia, Bianca Maria Nastri, Alessandra Monti, Nunzianna Doti, Gianluigi Franci, Anna De Filippis and Massimiliano Galdiero
Pharmaceuticals 2023, 16(4), 509; https://doi.org/10.3390/ph16040509 - 29 Mar 2023
Cited by 3 | Viewed by 1544
Abstract
In recent years, the resistance of pathogenic microorganisms to common antimicrobial agents has raised to a severe public health problem. The moderate and wise use of antimicrobials and the prevention of infections are the most effective strategies for decreasing the spread and development [...] Read more.
In recent years, the resistance of pathogenic microorganisms to common antimicrobial agents has raised to a severe public health problem. The moderate and wise use of antimicrobials and the prevention of infections are the most effective strategies for decreasing the spread and development of resistance. Therefore, the World Health Organization (WHO) has intensified the search for new drugs to fight emerging pathogens. Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), play a crucial role in innate immunity, representing one of the first line of defense against microbial attacks. In this study, we evaluated the antibacterial activity of the AMP named Hylin-a1 (derived from the skin of the frog Heleioporus albopunctatus) against Staphylococcus aureus strains. S. aureus represents a commensal bacterium but also the principal causative agent of several human infections, including bacteremia, endocarditis, skin and device-related infections. Hylin-a1 toxicity was evaluated on human keratinocytes; once the non-cytotoxic concentration range was determined, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were analyzed, and time-killing assays were performed to verify the bacteriostatic and/or bactericidal activity of the peptide. We found that Hylin-a1 exerted a bacteriostatic action against most of the tested strains, with 90% inhibition at the concentration of 6.25 μM. Noteworthy, the peptide at a very low concentration (~3 μM) significantly blocked the growth of β-lactam- and methicillin-resistant S. aureus. The levels of interleukin (IL)-1β, IL-6 and IL-8 were quantified through a molecular assay, indicating that the peptide was able also to regulate the inflammatory response following bacterial infection. The effect of Hylin-a1 on S. aureus cell morphology was also evaluated. Altogether, these results indicate the high therapeutic potential of Hylin-a1 against a wide variety of clinical manifestations caused by S. aureus. Full article
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Review

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34 pages, 1360 KiB  
Review
An Update on the Therapeutic Potential of Antimicrobial Peptides against Acinetobacter baumannii Infections
by Karyne Rangel, Guilherme Curty Lechuga, David W. Provance, Jr., Carlos M. Morel and Salvatore G. De Simone
Pharmaceuticals 2023, 16(9), 1281; https://doi.org/10.3390/ph16091281 - 11 Sep 2023
Cited by 3 | Viewed by 1550
Abstract
The rise in antibiotic-resistant strains of clinically important pathogens is a major threat to global health. The World Health Organization (WHO) has recognized the urgent need to develop alternative treatments to address the growing list of priority pathogens. Antimicrobial peptides (AMPs) rank among [...] Read more.
The rise in antibiotic-resistant strains of clinically important pathogens is a major threat to global health. The World Health Organization (WHO) has recognized the urgent need to develop alternative treatments to address the growing list of priority pathogens. Antimicrobial peptides (AMPs) rank among the suggested options with proven activity and high potential to be developed into effective drugs. Many AMPs are naturally produced by living organisms protecting the host against pathogens as a part of their innate immunity. Mechanisms associated with AMP actions include cell membrane disruption, cell wall weakening, protein synthesis inhibition, and interference in nucleic acid dynamics, inducing apoptosis and necrosis. Acinetobacter baumannii is a critical pathogen, as severe clinical implications have developed from isolates resistant to current antibiotic treatments and conventional control procedures, such as UV light, disinfectants, and drying. Here, we review the natural AMPs representing primary candidates for new anti-A. baumannii drugs in post-antibiotic-era and present computational tools to develop the next generation of AMPs with greater microbicidal activity and reduced toxicity. Full article
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31 pages, 2001 KiB  
Review
Age of Antibiotic Resistance in MDR/XDR Clinical Pathogen of Pseudomonas aeruginosa
by Ashish Kothari, Radhika Kherdekar, Vishal Mago, Madhur Uniyal, Garima Mamgain, Roop Bhushan Kalia, Sandeep Kumar, Neeraj Jain, Atul Pandey and Balram Ji Omar
Pharmaceuticals 2023, 16(9), 1230; https://doi.org/10.3390/ph16091230 - 30 Aug 2023
Cited by 1 | Viewed by 2236
Abstract
Antibiotic resistance in Pseudomonas aeruginosa remains one of the most challenging phenomena of everyday medical science. The universal spread of high-risk clones of multidrug-resistant/extensively drug-resistant (MDR/XDR) clinical P. aeruginosa has become a public health threat. The P. aeruginosa bacteria exhibits remarkable genome plasticity [...] Read more.
Antibiotic resistance in Pseudomonas aeruginosa remains one of the most challenging phenomena of everyday medical science. The universal spread of high-risk clones of multidrug-resistant/extensively drug-resistant (MDR/XDR) clinical P. aeruginosa has become a public health threat. The P. aeruginosa bacteria exhibits remarkable genome plasticity that utilizes highly acquired and intrinsic resistance mechanisms to counter most antibiotic challenges. In addition, the adaptive antibiotic resistance of P. aeruginosa, including biofilm-mediated resistance and the formation of multidrug-tolerant persisted cells, are accountable for recalcitrance and relapse of infections. We highlighted the AMR mechanism considering the most common pathogen P. aeruginosa, its clinical impact, epidemiology, and save our souls (SOS)-mediated resistance. We further discussed the current therapeutic options against MDR/XDR P. aeruginosa infections, and described those treatment options in clinical practice. Finally, other therapeutic strategies, such as bacteriophage-based therapy and antimicrobial peptides, were described with clinical relevance. Full article
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