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Creation of New Antimicrobial Peptides

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 94190

Special Issue Editor

1. Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Russia
2. Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia
Interests: protein folding; bioinformatics and proteomics; aggregation; Alzheimer’s disease; intrinsically disordered proteins; antibacterial peptides
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

World Health Organization (WHO) classifies polyresistant bacteria as a serious health hazard. In the last ten years, bacteria resistant to multiple drug dependences are have become a serious challenge for prophylactics and the treatment of many bacterial diseases. Available antibiotics are gradually becoming ineffective as a result of the resistance of bacterial cells, so it is necessary to find new antibacterial strategies to combat pathogenic organisms. Most new antibiotics are variants or combinations of existing therapeutic drugs. The world is faced with the problem of developing new strategies and technologies for combating pathogenic bacteria (bacterial diseases), and, on their basis, is creating new-generation antibacterial drugs. Around 12–17 microorganisms cause 80%–87% of nosocomial infections. Among them are S. aureus and P. aeruginosa. Among these pathogens, 16%–20% include multidrug-resistant phenotypes.

Antimicrobial peptides are diverse in terms of structure and mode of action, display broad-spectrum antimicrobial activity, and thus show promise for engineering pathogen resistance and development of novel pharmaceuticals. Novel antimicrobial peptides are under development. The creation of a novel technology and new antibiotics based on it will be a breakthrough in this field of research. The most decisive advantage of antibacterial peptides is the following: (1) the possibility to construct peptides of directional effect and (2) biological compatibility due to their natural origin.

In this Special Issue, the authors present new antimicrobial peptides and a new strategy for combating pathogenic microbes.

Prof. Dr. Oxana V. Galzitskaya
Guest Editor

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Keywords

  • anti-infective agents
  • antimicrobial peptide
  • bacterial infection
  • induced resistance.

Published Papers (23 papers)

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Editorial

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5 pages, 215 KiB  
Editorial
Creation of New Antimicrobial Peptides
by Oxana V. Galzitskaya
Int. J. Mol. Sci. 2023, 24(11), 9451; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119451 - 29 May 2023
Cited by 3 | Viewed by 1276
Abstract
Antimicrobial peptides (AMPs) are natural compounds that exhibit potent antimicrobial activity against various microorganisms, including bacteria, fungi, and viruses [...] Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)

Research

Jump to: Editorial, Review

17 pages, 3744 KiB  
Article
Model Amphipathic Peptide Coupled with Tacrine to Improve Its Antiproliferative Activity
by Sara Silva, Cláudia Alves, Diana Duarte, Ana Costa, Bruno Sarmento, António J. Almeida, Paula Gomes and Nuno Vale
Int. J. Mol. Sci. 2021, 22(1), 242; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010242 - 29 Dec 2020
Cited by 7 | Viewed by 2490
Abstract
Drug repurposing and drug combination are two strategies that have been widely used to overcome the traditional development of new anticancer drugs. Several FDA-approved drugs for other indications have been tested and have demonstrated beneficial anticancer effects. In this connection, our research group [...] Read more.
Drug repurposing and drug combination are two strategies that have been widely used to overcome the traditional development of new anticancer drugs. Several FDA-approved drugs for other indications have been tested and have demonstrated beneficial anticancer effects. In this connection, our research group recently reported that Tacrine, used to treat Alzheimer’s Disease, inhibits the growth of breast cancer MCF-7 cells both alone and in combination with a reference drug. In this view, we have now coupled Tacrine with the model amphipathic cell-penetrating peptide (CPP) MAP, to ascertain whether coupling of the CPP might enhance the drug’s antiproliferative properties. To this end, we synthesized MAP through solid-phase peptide synthesis, coupled it with Tacrine, and made a comparative evaluation of the parent drug, peptide, and the conjugate regarding their permeability across the blood-brain barrier (BBB), ability to inhibit acetylcholinesterase (AChE) in vitro, and antiproliferative activity on cancer cells. Both MAP and its Tacrine conjugate were highly toxic to MCF-7 and SH-SY5Y cells. In turn, BBB-permeability studies were inconclusive, and conjugation to the CPP led to a considerable loss of Tacrine function as an AChE inhibitor. Nonetheless, this work reinforces the potential of repurposing Tacrine for cancer and enhances the antiproliferative activity of this drug through its conjugation to a CPP. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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19 pages, 1713 KiB  
Article
EcDBS1R4, an Antimicrobial Peptide Effective against Escherichia coli with In Vitro Fusogenic Ability
by Marcin Makowski, Mário R. Felício, Isabel C. M. Fensterseifer, Octávio L. Franco, Nuno C. Santos and Sónia Gonçalves
Int. J. Mol. Sci. 2020, 21(23), 9104; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239104 - 30 Nov 2020
Cited by 11 | Viewed by 2561
Abstract
Discovering antibiotic molecules able to hold the growing spread of antimicrobial resistance is one of the most urgent endeavors that public health must tackle. The case of Gram-negative bacterial pathogens is of special concern, as they are intrinsically resistant to many antibiotics, due [...] Read more.
Discovering antibiotic molecules able to hold the growing spread of antimicrobial resistance is one of the most urgent endeavors that public health must tackle. The case of Gram-negative bacterial pathogens is of special concern, as they are intrinsically resistant to many antibiotics, due to an outer membrane that constitutes an effective permeability barrier. Antimicrobial peptides (AMPs) have been pointed out as potential alternatives to conventional antibiotics, as their main mechanism of action is membrane disruption, arguably less prone to elicit resistance in pathogens. Here, we investigate the in vitro activity and selectivity of EcDBS1R4, a bioinspired AMP. To this purpose, we have used bacterial cells and model membrane systems mimicking both the inner and the outer membranes of Escherichia coli, and a variety of optical spectroscopic methodologies. EcDBS1R4 is effective against the Gram-negative E. coli, ineffective against the Gram-positive Staphylococcus aureus and noncytotoxic for human cells. EcDBS1R4 does not form stable pores in E. coli, as the peptide does not dissipate its membrane potential, suggesting an unusual mechanism of action. Interestingly, EcDBS1R4 promotes a hemi-fusion of vesicles mimicking the inner membrane of E. coli. This fusogenic ability of EcDBS1R4 requires the presence of phospholipids with a negative curvature and a negative charge. This finding suggests that EcDBS1R4 promotes a large lipid spatial reorganization able to reshape membrane curvature, with interesting biological implications herein discussed. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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16 pages, 5058 KiB  
Article
Structural and Functional Enrichment Analyses for Antimicrobial Peptides
by Sheng C. Lo, Zhong-Ru Xie and Kuan Y. Chang
Int. J. Mol. Sci. 2020, 21(22), 8783; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228783 - 20 Nov 2020
Cited by 5 | Viewed by 1829
Abstract
Whether there is any inclination between structures and functions of antimicrobial peptides (AMPs) is a mystery yet to be unraveled. AMPs have various structures associated with many different antimicrobial functions, including antibacterial, anticancer, antifungal, antiparasitic and antiviral activities. However, none has yet reported [...] Read more.
Whether there is any inclination between structures and functions of antimicrobial peptides (AMPs) is a mystery yet to be unraveled. AMPs have various structures associated with many different antimicrobial functions, including antibacterial, anticancer, antifungal, antiparasitic and antiviral activities. However, none has yet reported any antimicrobial functional tendency within a specific category of protein/peptide structures nor any structural tendency of a specific antimicrobial function with respect to AMPs. Here, we examine the relationships between structures categorized by three structural classification methods (CATH, SCOP, and TM) and seven antimicrobial functions with respect to AMPs using an enrichment analysis. The results show that antifungal activities of AMPs were tightly related to the two-layer sandwich structure of CATH, the knottin fold of SCOP, and the first structural cluster of TM. The associations with knottin and TM Cluster 1 even sustained through the AMPs with a low sequence identity. Moreover, another significant mutual enrichment was observed between the third cluster of TM and anti-Gram-positive-bacterial/anti-Gram-negative-bacterial activities. The findings of the structure–function inclination further our understanding of AMPs and could help us design or discover new therapeutic potential AMPs. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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23 pages, 2782 KiB  
Article
Effects of Rationally Designed Physico-Chemical Variants of the Peptide PuroA on Biocidal Activity towards Bacterial and Mammalian Cells
by Nadin Shagaghi, Andrew H. A. Clayton, Marie-Isabel Aguilar, Tzong-Hsien Lee, Enzo A. Palombo and Mrinal Bhave
Int. J. Mol. Sci. 2020, 21(22), 8624; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228624 - 16 Nov 2020
Cited by 9 | Viewed by 1801
Abstract
Antimicrobial peptides (AMPs) often exhibit wide-spectrum activities and are considered ideal candidates for effectively controlling persistent and multidrug-resistant wound infections. PuroA, a synthetic peptide based on the tryptophan (Trp)-rich domain of the wheat protein puroindoline A, displays strong antimicrobial activities. In this work, [...] Read more.
Antimicrobial peptides (AMPs) often exhibit wide-spectrum activities and are considered ideal candidates for effectively controlling persistent and multidrug-resistant wound infections. PuroA, a synthetic peptide based on the tryptophan (Trp)-rich domain of the wheat protein puroindoline A, displays strong antimicrobial activities. In this work, a number of peptides were designed based on PuroA, varying in physico-chemical parameters of length, number of Trp residues, net charge, hydrophobicity or amphipathicity, D-versus L-isomers of amino acids, cyclization or dimerization, and were tested for antimicrobial potency and salt and protease tolerance. Selected peptides were assessed for effects on biofilms of methicillin-resistant Staphylococcus aureus (MRSA) and selected mammalian cells. Peptide P1, with the highest amphipathicity, six Trp and a net charge of +7, showed strong antimicrobial activity and salt stability. Peptides W7, W8 and WW (seven to eight residues) were generally more active than PuroA and all diastereomers were protease-resistant. PuroA and certain variants significantly inhibited initial biomass attachment and eradicated preformed biofilms of MRSA. Further, P1 and dimeric PuroA were cytotoxic to HeLa cells. The work has led to peptides with biocidal effects on common human pathogens and/or anticancer potential, also offering great insights into the relationship between physico-chemical parameters and bioactivities, accelerating progress towards rational design of AMPs for therapeutics. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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15 pages, 2378 KiB  
Article
Comparative Analysis of Proteomes of a Number of Nosocomial Pathogens by KEGG Modules and KEGG Pathways
by Mikhail V. Slizen and Oxana V. Galzitskaya
Int. J. Mol. Sci. 2020, 21(21), 7839; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217839 - 22 Oct 2020
Cited by 13 | Viewed by 2423
Abstract
Nosocomial (hospital-acquired) infections remain a serious challenge for health systems. The reason for this lies not only in the local imperfection of medical practices and protocols. The frequency of infection with antibiotic-resistant strains of bacteria is growing every year, both in developed and [...] Read more.
Nosocomial (hospital-acquired) infections remain a serious challenge for health systems. The reason for this lies not only in the local imperfection of medical practices and protocols. The frequency of infection with antibiotic-resistant strains of bacteria is growing every year, both in developed and developing countries. In this work, a pangenome and comparative analysis of 201 genomes of Staphylococcus aureus, Enterobacter spp., Pseudomonas aeruginosa, and Mycoplasma spp. was performed on the basis of high-level functional annotations—KEGG pathways and KEGG modules. The first three organisms are serious nosocomial pathogens, often exhibiting multidrug resistance. Analysis of KEGG modules revealed methicillin resistance in 25% of S. aureus strains and resistance to carbapenems in 21% of Enterobacter spp. strains. P. aeruginosa has a wide range of unique efflux systems. One hundred percent of the analyzed strains have at least two drug resistance systems, and 75% of the strains have seven. Each of the organisms has a characteristic set of metabolic features, whose impact on drug resistance can be considered in future studies. Comparing the genomes of nosocomial pathogens with each other and with Mycoplasma genomes can expand our understanding of the versatility of certain metabolic features and mechanisms of drug resistance. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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17 pages, 2827 KiB  
Article
Characterization of Cetacean Proline-Rich Antimicrobial Peptides Displaying Activity against ESKAPE Pathogens
by Riccardo Sola, Mario Mardirossian, Bertrand Beckert, Laura Sanghez De Luna, Dennis Prickett, Alessandro Tossi, Daniel N. Wilson and Marco Scocchi
Int. J. Mol. Sci. 2020, 21(19), 7367; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197367 - 06 Oct 2020
Cited by 7 | Viewed by 3356
Abstract
Proline-rich antimicrobial peptides (PrAMPs) may be a valuable weapon against multi-drug resistant pathogens, combining potent antimicrobial activity with low cytotoxicity. We have identified novel PrAMPs from five cetacean species (cePrAMPs), and characterized their potency, mechanism of action and in vitro cytotoxicity. Despite the [...] Read more.
Proline-rich antimicrobial peptides (PrAMPs) may be a valuable weapon against multi-drug resistant pathogens, combining potent antimicrobial activity with low cytotoxicity. We have identified novel PrAMPs from five cetacean species (cePrAMPs), and characterized their potency, mechanism of action and in vitro cytotoxicity. Despite the homology between the N-terminal of cePrAMPs and the bovine PrAMP Bac7, some differences emerged in their sequence, activity spectrum and mode of action. CePrAMPs with the highest similarity with the Bac7(1-35) fragment inhibited bacterial protein synthesis without membrane permeabilization, while a second subgroup of cePrAMPs was more membrane-active but less efficient at inhibiting bacterial translation. Such differences may be ascribable to differences in presence and positioning of Trp residues and of a conserved motif seemingly required for translation inhibition. Unlike Bac7(1-35), which requires the peptide transporter SbmA for its uptake, the activity of cePrAMPs was mostly independent of SbmA, regardless of their mechanism of action. Two peptides displayed a promisingly broad spectrum of activity, with minimal inhibiting concentration MIC ≤ 4 µM against several bacteria of the ESKAPE group, including Pseudomonas aeruginosa and Enterococcus faecium. Our approach has led us to discover several new peptides; correlating their sequences and mechanism of action will provide useful insights for designing optimized future peptide-based antibiotics. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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30 pages, 7780 KiB  
Article
Effect of Disulfide Cyclization of Ultrashort Cationic Lipopeptides on Antimicrobial Activity and Cytotoxicity
by Damian Neubauer, Maciej Jaśkiewicz, Emilia Sikorska, Sylwia Bartoszewska, Marta Bauer, Małgorzata Kapusta, Magdalena Narajczyk and Wojciech Kamysz
Int. J. Mol. Sci. 2020, 21(19), 7208; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197208 - 29 Sep 2020
Cited by 15 | Viewed by 3519
Abstract
Ultrashort cationic lipopeptides (USCLs) are considered to be a promising class of antimicrobials with high activity against a broad-spectrum of microorganisms. However, the majority of these compounds are characterized by significant toxicity toward human cells, which hinders their potential application. To overcome those [...] Read more.
Ultrashort cationic lipopeptides (USCLs) are considered to be a promising class of antimicrobials with high activity against a broad-spectrum of microorganisms. However, the majority of these compounds are characterized by significant toxicity toward human cells, which hinders their potential application. To overcome those limitations, several approaches have been advanced. One of these is disulfide cyclization that has been shown to improve drug-like characteristics of peptides. In this article the effect of disulfide cyclization of the polar head of N-palmitoylated USCLs on in vitro biological activity has been studied. Lipopeptides used in this study consisted of three or four basic amino acids (lysine and arginine) and cystine in a cyclic peptide. In general, disulfide cyclization of the lipopeptides resulted in peptides with reduced cytotoxicity. Disulfide-cyclized USCLs exhibited improved selectivity between Candida sp., Gram-positive strains and normal cells in contrast to their linear counterparts. Interactions between selected USCLs and membranes were studied by molecular dynamics simulations using a coarse-grained force field. Moreover, membrane permeabilization properties and kinetics were examined. Fluorescence and transmission electron microscopy revealed damage to Candida cell membrane and organelles. Concluding, USCLs are strong membrane disruptors and disulfide cyclization of polar head can have a beneficial effect on its in vitro selectivity between Candida sp. and normal human cells. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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14 pages, 1635 KiB  
Article
The Hirudo Medicinalis Microbiome Is a Source of New Antimicrobial Peptides
by Ekaterina Grafskaia, Elizaveta Pavlova, Vladislav V. Babenko, Ivan Latsis, Maja Malakhova, Victoria Lavrenova, Pavel Bashkirov, Dmitrii Belousov, Dmitry Klinov and Vassili Lazarev
Int. J. Mol. Sci. 2020, 21(19), 7141; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197141 - 27 Sep 2020
Cited by 11 | Viewed by 3034
Abstract
Antimicrobial peptides (AMPs) are considered a promising new class of anti-infectious agents. This study reports new antimicrobial peptides derived from the Hirudo medicinalis microbiome identified by a computational analysis method applied to the H. medicinalis metagenome. The identified AMPs possess a strong antimicrobial [...] Read more.
Antimicrobial peptides (AMPs) are considered a promising new class of anti-infectious agents. This study reports new antimicrobial peptides derived from the Hirudo medicinalis microbiome identified by a computational analysis method applied to the H. medicinalis metagenome. The identified AMPs possess a strong antimicrobial activity against Gram-positive and Gram-negative bacteria (MIC range: 5.3 to 22.4 μM), including Staphylococcus haemolyticus, an opportunistic coagulase–negative pathogen. The secondary structure analysis of peptides via CD spectroscopy showed that all the AMPs except pept_352 have mostly disordered structures that do not change under different conditions. For peptide pept_352, the α–helical content increases in the membrane environment. The examination of the mechanism of action of peptides suggests that peptide pept_352 exhibits a direct membranolytic activity. Furthermore, the cytotoxicity assay demonstrated that the nontoxic peptide pept_1545 is a promising candidate for drug development. Overall, the analysis method implemented in the study may serve as an effective tool for the identification of new AMPs. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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22 pages, 3889 KiB  
Article
A Safe and Multitasking Antimicrobial Decapeptide: The Road from De Novo Design to Structural and Functional Characterization
by Bruna Agrillo, Yolande T. R. Proroga, Marta Gogliettino, Marco Balestrieri, Rosarita Tatè, Luigi Nicolais and Gianna Palmieri
Int. J. Mol. Sci. 2020, 21(18), 6952; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186952 - 22 Sep 2020
Cited by 6 | Viewed by 2476
Abstract
Antimicrobial peptides (AMPs) are excellent candidates to fight multi-resistant pathogens worldwide and are considered promising bio-preservatives to control microbial spoilage through food processing. To date, designing de novo AMPs with high therapeutic indexes, low-cost synthesis, high resistance, and bioavailability, remains a challenge. In [...] Read more.
Antimicrobial peptides (AMPs) are excellent candidates to fight multi-resistant pathogens worldwide and are considered promising bio-preservatives to control microbial spoilage through food processing. To date, designing de novo AMPs with high therapeutic indexes, low-cost synthesis, high resistance, and bioavailability, remains a challenge. In this study, a novel decapeptide, named RiLK1, was rationally designed starting from the sequence of the previously characterized AMP 1018-K6, with the aim of developing short peptides, and promoting higher selectivity over mammalian cells, antibacterial activity, and structural resistance under different salt, pH, and temperature conditions. Interestingly, RiLK1 displayed a broad-spectrum of bactericidal activity against Gram-positive and Gram-negative bacteria, including multidrug resistant clinical isolates of Salmonella species, with Minimal Bactericidal Concentration (MBC) values in low micromolar range, and it was effective even against two fungal pathogens with no evidence of cytotoxicity on human keratinocytes and fibroblasts. Moreover, RiLK1-activated polypropylene films were revealed to efficiently prevent the growth of microbial spoilage, possibly improving the shelf life of fresh food products. These results suggested that de novo designed peptide RiLK1 could be the first candidate for the development of a promising class of decameric and multitask antimicrobial agents to overcome drug-resistance phenomena. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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19 pages, 4551 KiB  
Article
Antimicrobial and Amyloidogenic Activity of Peptides Synthesized on the Basis of the Ribosomal S1 Protein from Thermus Thermophilus
by Stanislav R. Kurpe, Sergei Yu. Grishin, Alexey K. Surin, Olga M. Selivanova, Roman S. Fadeev, Ulyana F. Dzhus, Elena Yu. Gorbunova, Leila G. Mustaeva, Vyacheslav N. Azev and Oxana V. Galzitskaya
Int. J. Mol. Sci. 2020, 21(17), 6382; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176382 - 02 Sep 2020
Cited by 18 | Viewed by 3067
Abstract
Controlling the aggregation of vital bacterial proteins could be one of the new research directions and form the basis for the search and development of antibacterial drugs with targeted action. Such approach may be considered as an alternative one to antibiotics. Amyloidogenic regions [...] Read more.
Controlling the aggregation of vital bacterial proteins could be one of the new research directions and form the basis for the search and development of antibacterial drugs with targeted action. Such approach may be considered as an alternative one to antibiotics. Amyloidogenic regions can, like antibacterial peptides, interact with the “parent” protein, for example, ribosomal S1 protein (specific only for bacteria), and interfere with its functioning. The aim of the work was to search for peptides based on the ribosomal S1 protein from T. thermophilus, exhibiting both aggregation and antibacterial properties. The biological system of the response of Gram-negative bacteria T. thermophilus to the action of peptides was characterized. Among the seven studied peptides, designed based on the S1 protein sequence, the R23I (modified by the addition of HIV transcription factor fragment for bacterial cell penetration), R23T (modified), and V10I (unmodified) peptides have biological activity that inhibits the growth of T. thermophilus cells, that is, they have antimicrobial activity. But, only the R23I peptide had the most pronounced activity comparable with the commercial antibiotics. We have compared the proteome of peptide-treated and intact T. thermophilus cells. These important data indicate a decrease in the level of energy metabolism and anabolic processes, including the processes of biosynthesis of proteins and nucleic acids. Under the action of 20 and 50 μg/mL R23I, a decrease in the number of proteins in T. thermophilus cells was observed and S1 ribosomal protein was absent. The obtained results are important for understanding the mechanism of amyloidogenic peptides with antimicrobial activity and can be used to develop new and improved analogues. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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24 pages, 6550 KiB  
Article
A Novel Peptide Antibiotic, Pro10-1D, Designed from Insect Defensin Shows Antibacterial and Anti-Inflammatory Activities in Sepsis Models
by Manigandan Krishnan, Joonhyeok Choi, Ahjin Jang and Yangmee Kim
Int. J. Mol. Sci. 2020, 21(17), 6216; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176216 - 27 Aug 2020
Cited by 23 | Viewed by 5429
Abstract
Owing to the challenges faced by conventional therapeutics, novel peptide antibiotics against multidrug-resistant (MDR) gram-negative bacteria need to be urgently developed. We had previously designed Pro9-3 and Pro9-3D from the defensin of beetle Protaetia brevitarsis; they showed high antimicrobial activity with cytotoxicity. [...] Read more.
Owing to the challenges faced by conventional therapeutics, novel peptide antibiotics against multidrug-resistant (MDR) gram-negative bacteria need to be urgently developed. We had previously designed Pro9-3 and Pro9-3D from the defensin of beetle Protaetia brevitarsis; they showed high antimicrobial activity with cytotoxicity. Here, we aimed to develop peptide antibiotics with bacterial cell selectivity and potent antibacterial activity against gram-negative bacteria. We designed 10-meric peptides with increased cationicity by adding Arg to the N-terminus of Pro9-3 (Pro10-1) and its D-enantiomeric alteration (Pro10-1D). Among all tested peptides, the newly designed Pro10-1D showed the strongest antibacterial activity against Escherichia coli, Acinetobacter baumannii, and MDR strains with resistance against protease digestion. Pro10-1D can act as a novel potent peptide antibiotic owing to its outstanding inhibitory activities against bacterial film formation with high bacterial cell selectivity. Dye leakage and scanning electron microscopy revealed that Pro10-1D targets the bacterial membrane. Pro10-1D inhibited inflammation via Toll Like Receptor 4 (TLR4)/Nuclear factor-κB (NF-κB) signaling pathways in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Furthermore, Pro10-1D ameliorated multiple-organ damage and attenuated systemic infection-associated inflammation in an E. coli K1-induced sepsis mouse model. Overall, our results suggest that Pro10-1D can potentially serve as a novel peptide antibiotic for the treatment of gram-negative sepsis. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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18 pages, 2715 KiB  
Article
Antimicrobial Activity of Small Synthetic Peptides Based on the Marine Peptide Turgencin A: Prediction of Antimicrobial Peptide Sequences in a Natural Peptide and Strategy for Optimization of Potency
by Ida K. Ø. Hansen, Tomas Lövdahl, Danijela Simonovic, Kine Ø. Hansen, Aaron J. C. Andersen, Hege Devold, Céline S. M. Richard, Jeanette H. Andersen, Morten B. Strøm and Tor Haug
Int. J. Mol. Sci. 2020, 21(15), 5460; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155460 - 30 Jul 2020
Cited by 28 | Viewed by 4817
Abstract
Turgencin A, a potent antimicrobial peptide isolated from the Arctic sea squirt Synoicum turgens, consists of 36 amino acid residues and three disulfide bridges, making it challenging to synthesize. The aim of the present study was to develop a truncated peptide with [...] Read more.
Turgencin A, a potent antimicrobial peptide isolated from the Arctic sea squirt Synoicum turgens, consists of 36 amino acid residues and three disulfide bridges, making it challenging to synthesize. The aim of the present study was to develop a truncated peptide with an antimicrobial drug lead potential based on turgencin A. The experiments consisted of: (1) sequence analysis and prediction of antimicrobial potential of truncated 10-mer sequences; (2) synthesis and antimicrobial screening of a lead peptide devoid of the cysteine residues; (3) optimization of in vitro antimicrobial activity of the lead peptide using an amino acid replacement strategy; and (4) screening the synthesized peptides for cytotoxic activities. In silico analysis of turgencin A using various prediction software indicated an internal, cationic 10-mer sequence to be putatively antimicrobial. The synthesized truncated lead peptide displayed weak antimicrobial activity. However, by following a systematic amino acid replacement strategy, a modified peptide was developed that retained the potency of the original peptide. The optimized peptide StAMP-9 displayed bactericidal activity, with minimal inhibitory concentrations of 7.8 µg/mL against Staphylococcus aureus and 3.9 µg/mL against Escherichia coli, and no cytotoxic effects against mammalian cells. Preliminary experiments indicate the bacterial membranes as immediate and primary targets. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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19 pages, 2583 KiB  
Article
Amyloidogenic Propensities of Ribosomal S1 Proteins: Bioinformatics Screening and Experimental Checking
by Sergei Y. Grishin, Evgeniya I. Deryusheva, Andrey V. Machulin, Olga M. Selivanova, Anna V. Glyakina, Elena Y. Gorbunova, Leila G. Mustaeva, Vyacheslav N. Azev, Valentina V. Rekstina, Tatyana S. Kalebina, Alexey K. Surin and Oxana V. Galzitskaya
Int. J. Mol. Sci. 2020, 21(15), 5199; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155199 - 22 Jul 2020
Cited by 16 | Viewed by 2866
Abstract
Structural S1 domains belong to the superfamily of oligosaccharide/oligonucleotide-binding fold domains, which are highly conserved from prokaryotes to higher eukaryotes and able to function in RNA binding. An important feature of this family is the presence of several copies of the structural domain, [...] Read more.
Structural S1 domains belong to the superfamily of oligosaccharide/oligonucleotide-binding fold domains, which are highly conserved from prokaryotes to higher eukaryotes and able to function in RNA binding. An important feature of this family is the presence of several copies of the structural domain, the number of which is determined in a strictly limited range from one to six. Despite the strong tendency for the aggregation of several amyloidogenic regions in the family of the ribosomal S1 proteins, their fibril formation process is still poorly understood. Here, we combined computational and experimental approaches for studying some features of the amyloidogenic regions in this protein family. The FoldAmyloid, Waltz, PASTA 2.0 and Aggrescan programs were used to assess the amyloidogenic propensities in the ribosomal S1 proteins and to identify such regions in various structural domains. The thioflavin T fluorescence assay and electron microscopy were used to check the chosen amyloidogenic peptides’ ability to form fibrils. The bioinformatics tools were used to study the amyloidogenic propensities in 1331 ribosomal S1 proteins. We found that amyloidogenicity decreases with increasing sizes of proteins. Inside one domain, the amyloidogenicity is higher in the terminal parts. We selected and synthesized 11 amyloidogenic peptides from the Escherichia coli and Thermus thermophilus ribosomal S1 proteins and checked their ability to form amyloids using the thioflavin T fluorescence assay and electron microscopy. All 11 amyloidogenic peptides form amyloid-like fibrils. The described specific amyloidogenic regions are actually responsible for the fibrillogenesis process and may be potential targets for modulating the amyloid properties of bacterial ribosomal S1 proteins. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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20 pages, 4887 KiB  
Article
Molecular Characterization of a Novel Lytic Enzyme LysC from Clostridium intestinale URNW and Its Antibacterial Activity Mediated by Positively Charged N-Terminal Extension
by Magdalena Plotka, Monika Szadkowska, Maria Håkansson, Rebeka Kovačič, Salam Al-Karadaghi, Björn Walse, Olesia Werbowy, Anna-Karina Kaczorowska and Tadeusz Kaczorowski
Int. J. Mol. Sci. 2020, 21(14), 4894; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144894 - 11 Jul 2020
Cited by 16 | Viewed by 3225
Abstract
Peptidoglycan hydrolytic enzymes are considered to be a promising alternative to conventional antibiotics in combating bacterial infections. To identify novel hydrolytic enzymes, we performed a database search with the sequences of two thermostable endolysins with high bactericidal activity, studied earlier in our laboratory. [...] Read more.
Peptidoglycan hydrolytic enzymes are considered to be a promising alternative to conventional antibiotics in combating bacterial infections. To identify novel hydrolytic enzymes, we performed a database search with the sequences of two thermostable endolysins with high bactericidal activity, studied earlier in our laboratory. Both these enzymes originate from Thermus scotoductus bacteriophages MAT2119 and vB_Tsc2631. A lytic enzyme LysC from Clostridium intestinale URNW was found to have the highest amino acid sequence similarity to the bacteriophage proteins and was chosen for further analysis. The recombinant enzyme showed strong activity against its host bacteria C. intestinale, as well as against C. sporogenes, Bacillus cereus, Micrococcus luteus, and Staphylococcus aureus, on average causing a 5.12 ± 0.14 log reduction of viable S. aureus ATCC 25923 cells in a bactericidal assay. Crystallographic studies of the protein showed that the catalytic site of LysC contained a zinc atom coordinated by amino acid residues His50, His147, and Cys155, a feature characteristic for type 2 amidases. Surprisingly, neither of these residues, nor any other of the four conserved residues in the vicinity of the active site, His51, Thr52, Tyr76, and Thr153, were essential to maintain the antibacterial activity of LysC. Therefore, our attention was attracted to the intrinsically disordered and highly positively charged N-terminal region of the enzyme. Potential antibacterial activity of this part of the sequence, predicted by the Antimicrobial Sequence Scanning System, AMPA, was confirmed in our experimental studies; the truncated version of LysC (LysCΔ2–23) completely lacked antibacterial activity. Moreover, a synthetic peptide, which we termed Intestinalin, with a sequence identical to the first thirty amino acids of LysC, displayed substantial anti-staphylococcal activity with IC50 of 6 μg/mL (1.5 μM). This peptide was shown to have α-helical conformation in solution in the presence of detergents which is a common feature of amphipathic α-helical antimicrobial peptides. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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13 pages, 2788 KiB  
Article
Potential Application of Protamine for Antimicrobial Biomaterials in Bone Tissue Engineering
by Michiyo Honda, Morio Matsumoto and Mamoru Aizawa
Int. J. Mol. Sci. 2020, 21(12), 4368; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124368 - 19 Jun 2020
Cited by 15 | Viewed by 2816
Abstract
Bacterial infection of biomaterials is a serious problem in the field of medical devices. It is urgently necessary to develop new biomaterials with bactericidal activity. Antimicrobial peptides and proteins (AMPs), alternative antibacterial agents, are expected to overcome the bacterial resistance. The aim of [...] Read more.
Bacterial infection of biomaterials is a serious problem in the field of medical devices. It is urgently necessary to develop new biomaterials with bactericidal activity. Antimicrobial peptides and proteins (AMPs), alternative antibacterial agents, are expected to overcome the bacterial resistance. The aim of this study was to develop a new intelligent material in bone tissue engineering based on protamine-loaded hydroxyapatite (protamine/HAp) that uses AMPs rather than antibiotics. It was found that the adsorption of protamine to HAp followed the Langmuir adsorption model and was due to electrostatic and/or hydrophobic interactions. In vitro bacterial adhesion and growth on protamine/HAp was inhibited in a protamine dose-dependent manner. Adherent bacteria exhibited an aberrant morphology for high dosages of protamine/HAp, resulting in the formation of large aggregates and disintegration of the membrane. The released protamine from protamine/HAp also prevented the growth of planktonic bacteria in vitro. However, a high dosage of protamine from powders at loading concentrations over 1000 μg·mL−1 induced a cytotoxic effect in vitro, although those exhibited no apparent cytotoxicity in vivo. These data revealed that protamine/HAp (less than 1000 μg·mL−1) had both antimicrobial activity and biocompatibility and can be applied for bone substitutes in orthopedic fields. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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13 pages, 426 KiB  
Article
Proteomic Screening for Prediction and Design of Antimicrobial Peptides with AmpGram
by Michał Burdukiewicz, Katarzyna Sidorczuk, Dominik Rafacz, Filip Pietluch, Jarosław Chilimoniuk, Stefan Rödiger and Przemysław Gagat
Int. J. Mol. Sci. 2020, 21(12), 4310; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124310 - 17 Jun 2020
Cited by 48 | Viewed by 4681
Abstract
Antimicrobial peptides (AMPs) are molecules widespread in all branches of the tree of life that participate in host defense and/or microbial competition. Due to their positive charge, hydrophobicity and amphipathicity, they preferentially disrupt negatively charged bacterial membranes. AMPs are considered an important alternative [...] Read more.
Antimicrobial peptides (AMPs) are molecules widespread in all branches of the tree of life that participate in host defense and/or microbial competition. Due to their positive charge, hydrophobicity and amphipathicity, they preferentially disrupt negatively charged bacterial membranes. AMPs are considered an important alternative to traditional antibiotics, especially at the time when multidrug-resistant bacteria being on the rise. Therefore, to reduce the costs of experimental research, robust computational tools for AMP prediction and identification of the best AMP candidates are essential. AmpGram is our novel tool for AMP prediction; it outperforms top-ranking AMP classifiers, including AMPScanner, CAMPR3R and iAMPpred. It is the first AMP prediction tool created for longer AMPs and for high-throughput proteomic screening. AmpGram prediction reliability was confirmed on the example of lactoferrin and thrombin. The former is a well known antimicrobial protein and the latter a cryptic one. Both proteins produce (after protease treatment) functional AMPs that have been experimentally validated at molecular level. The lactoferrin and thrombin AMPs were located in the antimicrobial regions clearly detected by AmpGram. Moreover, AmpGram also provides a list of shot 10 amino acid fragments in the antimicrobial regions, along with their probability predictions; these can be used for further studies and the rational design of new AMPs. AmpGram is available as a web-server, and an easy-to-use R package for proteomic analysis at CRAN repository. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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16 pages, 3130 KiB  
Article
Hybridization with Insect Cecropin A (1–8) Improve the Stability and Selectivity of Naturally Occurring Peptides
by Yang Yang, Di Wu, Chenxi Wang, Anshan Shan, Chongpeng Bi, Yanbing Li and Wenping Gan
Int. J. Mol. Sci. 2020, 21(4), 1470; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041470 - 21 Feb 2020
Cited by 20 | Viewed by 2763
Abstract
Antimicrobial peptides (AMPs) offer great hope and a promising opportunity to overcome the rapid development of drug-resistant pathogenic microbes. However, AMPs often lack the stability required for a successful systemic drug. Hybridizing different AMPs is a simple and effective strategy to obtain novel [...] Read more.
Antimicrobial peptides (AMPs) offer great hope and a promising opportunity to overcome the rapid development of drug-resistant pathogenic microbes. However, AMPs often lack the stability required for a successful systemic drug. Hybridizing different AMPs is a simple and effective strategy to obtain novel peptides. N-terminal fragment of cecropin A (CA (1-8)) is often used to hybridize with other AMPs to reduce cytotoxicity. However, hybridizing with CA (1-8) in improving the stability of AMPs is not clear. Therefore, a series of peptides were designed by combining with CA (1–8) and their antibacterial activity and stability in the presence of salts and human serum were evaluated. The resultant α-helical hybrid peptide CA-FO composed of CA (1-8) and the most potent region of Fowlicidin-2 (FO (1–15)) exhibited excellent antibacterial activity (2-8 μM) and cell selectivity toward bacterial over mammalian cells. Moreover, CA-FO still retained vigorous antimicrobial activity in the presence of human serum and salts at physiological concentrations. CA-FO exhibited effective antibacterial activity by increasing membrane permeability and damaging membrane integrity. In conclusion, these results indicated the success of hybridization in designing and optimizing AMPs with improved stability and selectivity and the peptide CA-FO can be further evaluated as peptide-therapy to treat bacterial infections. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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Review

Jump to: Editorial, Research

14 pages, 1141 KiB  
Review
Lipidation of Antimicrobial Peptides as a Design Strategy for Future Alternatives to Antibiotics
by Taylor Rounds and Suzana K. Straus
Int. J. Mol. Sci. 2020, 21(24), 9692; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249692 - 18 Dec 2020
Cited by 36 | Viewed by 3597
Abstract
Multi-drug-resistant bacteria are becoming more prevalent, and treating these bacteria is becoming a global concern. One alternative approach to combat bacterial resistance is to use antimicrobial (AMPs) or host-defense peptides (HDPs) because they possess broad-spectrum activity, function in a variety of ways, and [...] Read more.
Multi-drug-resistant bacteria are becoming more prevalent, and treating these bacteria is becoming a global concern. One alternative approach to combat bacterial resistance is to use antimicrobial (AMPs) or host-defense peptides (HDPs) because they possess broad-spectrum activity, function in a variety of ways, and lead to minimal resistance. However, the therapeutic efficacy of HDPs is limited by a number of factors, including systemic toxicity, rapid degradation, and low bioavailability. One approach to circumvent these issues is to use lipidation, i.e., the attachment of one or more fatty acid chains to the amine groups of the N-terminus or a lysine residue of an HDP. In this review, we examined lipidated analogs of 66 different HDPs reported in the literature to determine: (i) whether there is a link between acyl chain length and antibacterial activity; (ii) whether the charge and (iii) the hydrophobicity of the HDP play a role; and (iv) whether acyl chain length and toxicity are related. Overall, the analysis suggests that lipidated HDPs with improved activity over the nonlipidated counterpart had acyl chain lengths of 8–12 carbons. Moreover, active lipidated peptides attached to short HDPs tended to have longer acyl chain lengths. Neither the charge of the parent HDP nor the percent hydrophobicity of the peptide had an apparent significant impact on the antibacterial activity. Finally, the relationship between acyl chain length and toxicity was difficult to determine due to the fact that toxicity is quantified in different ways. The impact of these trends, as well as combined strategies such as the incorporation of d- and non-natural amino acids or alternative approaches, will be discussed in light of how lipidation may play a role in the future development of antimicrobial peptide-based alternatives to current therapeutics. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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37 pages, 2860 KiB  
Review
Antimicrobial and Amyloidogenic Activity of Peptides. Can Antimicrobial Peptides Be Used against SARS-CoV-2?
by Stanislav R. Kurpe, Sergei Yu. Grishin, Alexey K. Surin, Alexander V. Panfilov, Mikhail V. Slizen, Saikat D. Chowdhury and Oxana V. Galzitskaya
Int. J. Mol. Sci. 2020, 21(24), 9552; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249552 - 15 Dec 2020
Cited by 40 | Viewed by 5678
Abstract
At present, much attention is paid to the use of antimicrobial peptides (AMPs) of natural and artificial origin to combat pathogens. AMPs have several points that determine their biological activity. We analyzed the structural properties of AMPs, as well as described their mechanism [...] Read more.
At present, much attention is paid to the use of antimicrobial peptides (AMPs) of natural and artificial origin to combat pathogens. AMPs have several points that determine their biological activity. We analyzed the structural properties of AMPs, as well as described their mechanism of action and impact on pathogenic bacteria and viruses. Recently published data on the development of new AMP drugs based on a combination of molecular design and genetic engineering approaches are presented. In this article, we have focused on information on the amyloidogenic properties of AMP. This review examines AMP development strategies from the perspective of the current high prevalence of antibiotic-resistant bacteria, and the potential prospects and challenges of using AMPs against infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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45 pages, 11744 KiB  
Review
The Best Peptidomimetic Strategies to Undercover Antibacterial Peptides
by Joanna Izabela Lachowicz, Kacper Szczepski, Alessandra Scano, Cinzia Casu, Sara Fais, Germano Orrù, Barbara Pisano, Monica Piras and Mariusz Jaremko
Int. J. Mol. Sci. 2020, 21(19), 7349; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197349 - 05 Oct 2020
Cited by 25 | Viewed by 5120
Abstract
Health-care systems that develop rapidly and efficiently may increase the lifespan of humans. Nevertheless, the older population is more fragile, and is at an increased risk of disease development. A concurrently growing number of surgeries and transplantations have caused antibiotics to be used [...] Read more.
Health-care systems that develop rapidly and efficiently may increase the lifespan of humans. Nevertheless, the older population is more fragile, and is at an increased risk of disease development. A concurrently growing number of surgeries and transplantations have caused antibiotics to be used much more frequently, and for much longer periods of time, which in turn increases microbial resistance. In 1945, Fleming warned against the abuse of antibiotics in his Nobel lecture: “The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant”. After 70 years, we are witnessing the fulfilment of Fleming’s prophecy, as more than 700,000 people die each year due to drug-resistant diseases. Naturally occurring antimicrobial peptides protect all living matter against bacteria, and now different peptidomimetic strategies to engineer innovative antibiotics are being developed to defend humans against bacterial infections. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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23 pages, 2766 KiB  
Review
A New Era of Antibiotics: The Clinical Potential of Antimicrobial Peptides
by Katrina Browne, Sudip Chakraborty, Renxun Chen, Mark DP Willcox, David StClair Black, William R Walsh and Naresh Kumar
Int. J. Mol. Sci. 2020, 21(19), 7047; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197047 - 24 Sep 2020
Cited by 213 | Viewed by 20197
Abstract
Antimicrobial resistance is a multifaceted crisis, imposing a serious threat to global health. The traditional antibiotic pipeline has been exhausted, prompting research into alternate antimicrobial strategies. Inspired by nature, antimicrobial peptides are rapidly gaining attention for their clinical potential as they present distinct [...] Read more.
Antimicrobial resistance is a multifaceted crisis, imposing a serious threat to global health. The traditional antibiotic pipeline has been exhausted, prompting research into alternate antimicrobial strategies. Inspired by nature, antimicrobial peptides are rapidly gaining attention for their clinical potential as they present distinct advantages over traditional antibiotics. Antimicrobial peptides are found in all forms of life and demonstrate a pivotal role in the innate immune system. Many antimicrobial peptides are evolutionarily conserved, with limited propensity for resistance. Additionally, chemical modifications to the peptide backbone can be used to improve biological activity and stability and reduce toxicity. This review details the therapeutic potential of peptide-based antimicrobials, as well as the challenges needed to overcome in order for clinical translation. We explore the proposed mechanisms of activity, design of synthetic biomimics, and how this novel class of antimicrobial compound may address the need for effective antibiotics. Finally, we discuss commercially available peptide-based antimicrobials and antimicrobial peptides in clinical trials. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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22 pages, 2347 KiB  
Review
Design, Engineering and Discovery of Novel α-Helical and β-Boomerang Antimicrobial Peptides against Drug Resistant Bacteria
by Surajit Bhattacharjya and Suzana K. Straus
Int. J. Mol. Sci. 2020, 21(16), 5773; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165773 - 11 Aug 2020
Cited by 44 | Viewed by 3611
Abstract
In an era where the pipeline of new antibiotic development is drying up, the continuous rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) bacteria are genuine threats to human health. Although antimicrobial peptides (AMPs) may serve as promising leads against drug [...] Read more.
In an era where the pipeline of new antibiotic development is drying up, the continuous rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) bacteria are genuine threats to human health. Although antimicrobial peptides (AMPs) may serve as promising leads against drug resistant bacteria, only a few AMPs are in advanced clinical trials. The limitations of AMPs, namely their low in vivo activity, toxicity, and poor bioavailability, need to be addressed. Here, we review engineering of frog derived short α-helical AMPs (aurein, temporins) and lipopolysaccharide (LPS) binding designed β-boomerang AMPs for further development. The discovery of novel cell selective AMPs from the human proprotein convertase furin is also discussed. Full article
(This article belongs to the Special Issue Creation of New Antimicrobial Peptides)
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