Attacins: A Promising Class of Insect Antimicrobial Peptides

Insects produce a large repertoire of antimicrobial peptides (AMPs) as the first line of defense against bacteria, viruses, fungi or parasites. These peptides are produced from a large precursor that contains a signal domain, which is cleaved in vivo to produce the mature protein with antimicrobial activity. At present, AMPs from insects include several families which can be classified as cecropins, ponericins, defensins, lebocins, drosocin, Metchnikowin, gloverins, diptericins and attacins according to their structure and/or function. This short review is focused on attacins, a class of glycine-rich peptides/proteins that have been first discovered in the cecropia moth (Hyalophora cecropia). They are a rather heterogeneous group of immunity-related proteins that exhibit an antimicrobial effect mainly against Gram-negative bacteria. Here, we discuss different attacin and attacin-like AMPs that have been discovered so far and analyze their structure and phylogeny. Special focus is given to the physiological importance and mechanism of action of attacins against microbial pathogens together with their potential pharmacological applications, emphasizing their roles as antimicrobials.

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Multiple Antimicrobial Effects of Hybrid Peptides Synthesized Based on the Sequence of Ribosomal S1 Protein from Staphylococcus aureus

International Journal of Molecular Sciences ◽

10.3390/ijms23010524 ◽

2022 ◽

Vol 23 (1) ◽

pp. 524

Author(s):

Sergey V. Kravchenko ◽

Pavel A. Domnin ◽

Sergei Y. Grishin ◽

Alexander V. Panfilov ◽

Viacheslav N. Azev ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antimicrobial Peptides ◽

Pathogenic Bacteria ◽

Antimicrobial Effect ◽

Cell Penetrating Peptide ◽

Gram Negative Bacteria ◽

Antimicrobial Effects ◽

Bacterial Proteins ◽

Hybrid Peptides ◽

Successful Approach

The need to develop new antimicrobial peptides is due to the high resistance of pathogenic bacteria to traditional antibiotics now and in the future. The creation of synthetic peptide constructs is a common and successful approach to the development of new antimicrobial peptides. In this work, we use a simple, flexible, and scalable technique to create hybrid antimicrobial peptides containing amyloidogenic regions of the ribosomal S1 protein from Staphylococcus aureus. While the cell-penetrating peptide allows the peptide to enter the bacterial cell, the amyloidogenic site provides an antimicrobial effect by coaggregating with functional bacterial proteins. We have demonstrated the antimicrobial effects of the R23F, R23DI, and R23EI hybrid peptides against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa, Escherichia coli, and Bacillus cereus. R23F, R23DI, and R23EI can be used as antimicrobial peptides against Gram-positive and Gram-negative bacteria resistant to traditional antibiotics.

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Synergy and remarkable specificity of antimicrobial peptides in vivo using a systematic knockout approach

eLife ◽

10.7554/elife.44341 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 29

Author(s):

Mark Austin Hanson ◽

Anna Dostálová ◽

Camilla Ceroni ◽

Mickael Poidevin ◽

Shu Kondo ◽

...

Keyword(s):

Antimicrobial Peptides ◽

Fungal Pathogens ◽

Gene Editing ◽

Cationic Peptides ◽

Gram Negative Bacteria ◽

Biological Processes ◽

Gram Negative ◽

Bacteria And Fungi

Antimicrobial peptides (AMPs) are host-encoded antibiotics that combat invading microorganisms. These short, cationic peptides have been implicated in many biological processes, primarily involving innate immunity. In vitro studies have shown AMPs kill bacteria and fungi at physiological concentrations, but little validation has been done in vivo. We utilized CRISPR gene editing to delete most known immune-inducible AMPs of Drosophila, namely: 4 Attacins, 2 Diptericins, Drosocin, Drosomycin, Metchnikowin and Defensin. Using individual and multiple knockouts, including flies lacking these ten AMP genes, we characterize the in vivo function of individual and groups of AMPs against diverse bacterial and fungal pathogens. We found that Drosophila AMPs act primarily against Gram-negative bacteria and fungi, contributing either additively or synergistically. We also describe remarkable specificity wherein certain AMPs contribute the bulk of microbicidal activity against specific pathogens, providing functional demonstrations of highly specific AMP-pathogen interactions in an in vivo setting.

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Radiolabeled GRPR Antagonists for Imaging of Disseminated Prostate Cancer - Influence of Labeling Chemistry on Targeting Properties

Current Medicinal Chemistry ◽

10.2174/0929867327666200312114902 ◽

2020 ◽

Vol 27 (41) ◽

pp. 7090-7111 ◽

Cited By ~ 2

Author(s):

Bogdan Mitran ◽

Vladimir Tolmachev ◽

Anna Orlova

Keyword(s):

Prostate Cancer ◽

Molecular Imaging ◽

Rational Design ◽

Molecular Design ◽

Short Review ◽

Special Focus ◽

Strong Impact ◽

Blood Proteins ◽

Normal Tissues

Background: Radionuclide molecular imaging of Gastrin-Releasing Peptide Receptor (GRPR) expression promises unparalleled opportunities for visualizing subtle prostate tumors, which due to small size, adjacent benign tissue, or a challenging location would otherwise remain undetected by conventional imaging. Achieving high imaging contrast is essential for this purpose and the molecular design of any probe for molecular imaging of prostate cancer should be aimed at obtaining as high tumor-to-organ ratios as possible. Objective: This short review summarizes the key imaging modalities currently used in prostate cancer, with a special focus on radionuclide molecular imaging. Emphasis is laid mainly on the issue of radiometals labeling chemistry and its influence on the targeting properties and biodistribution of radiolabeled GRPR antagonists for imaging of disseminated prostate cancer. Methods: A comprehensive literature search of the PubMed/MEDLINE, and Scopus library databases was conducted to find relevant articles. Results: The combination of radionuclide, chelator and required labeling chemistry was shown to have a significant influence on the stability, binding affinity and internalization rate, off-target interaction with normal tissues and blood proteins, interaction with enzymes, activity uptake and retention in excretory organs and activity uptake in tumors of radiolabeled bombesin antagonistic analogues. Conclusion: Labeling chemistry has a very strong impact on the biodistribution profile of GRPRtargeting peptide based imaging probes and needs to be considered when designing a targeting probe for high contrast molecular imaging. Taking into account the complexity of in vivo interactions, it is not currently possible to accurately predict the optimal labeling approach. Therefore, a detailed in vivo characterization and optimization is essential for the rational design of imaging agents.

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Lipidation of Temporin-1CEb Derivatives as a Tool for Activity Improvement, Pros and Cons of the Approach

International Journal of Molecular Sciences ◽

10.3390/ijms22136679 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6679

Author(s):

Paulina Kosikowska-Adamus ◽

Emilia Sikorska ◽

Dariusz Wyrzykowski ◽

Aleksandra Walewska ◽

Anna Golda ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antimicrobial Peptides ◽

Antimicrobial Properties ◽

Carbon Chain ◽

Microbial Pathogens ◽

Multi Drug Resistance ◽

Aggregation State ◽

Conventional Antibiotics ◽

Biofilm Development

The alarming raise of multi-drug resistance among human microbial pathogens makes the development of novel therapeutics a priority task. In contrast to conventional antibiotics, antimicrobial peptides (AMPs), besides evoking a broad spectrum of activity against microorganisms, could offer additional benefits, such as the ability to neutralize toxins, modulate inflammatory response, eradicate bacterial and fungal biofilms or prevent their development. The latter properties are of special interest, as most antibiotics available on the market have limited ability to diffuse through rigid structures of biofilms. Lipidation of AMPs is considered as an effective approach for enhancement of their antimicrobial potential and in vivo stability; however, it could also have undesired impact on selectivity, solubility or the aggregation state of the modified peptides. In the present work, we describe the results of structural modifications of compounds designed based on cationic antimicrobial peptides DK5 and CAR-PEG-DK5, derivatized at their N-terminal part with fatty acids with different lengths of carbon chain. The proposed modifications substantially improved antimicrobial properties of the final compounds and their effectiveness in inhibition of biofilm development as well as eradication of pre-formed 24 h old biofilms of Candida albicans and Staphylococcus aureus. The most active compounds (C5-DK5, C12-DK5 and C12-CAR-PEG-DK5) were also potent against multi-drug resistant Staphylococcus aureus USA300 strain and clinical isolates of Pseudomonas aeruginosa. Both experimental and in silico methods revealed strong correlation between the length of fatty acid attached to the peptides and their final membranolytic properties, tendency to self-assemble and cytotoxicity.

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Synergy and remarkable specificity of antimicrobial peptides in vivo using a systematic knockout approach

10.1101/493817 ◽

2018 ◽

Cited By ~ 1

Author(s):

Mark Austin Hanson ◽

Anna Dostalova ◽

Camilla Ceroni ◽

Mickael Poidevin ◽

Shu Kondo ◽

...

Keyword(s):

Antimicrobial Peptides ◽

Fungal Pathogens ◽

Gene Editing ◽

Cationic Peptides ◽

Gram Negative Bacteria ◽

Biological Processes ◽

Gram Negative ◽

Bacteria And Fungi

Antimicrobial peptides (AMPs) are host-encoded antibiotics that combat invading microorganisms. These short, cationic peptides have been implicated in many biological processes, primarily involving innate immunity. In vitro studies have shown AMPs kill bacteria and fungi at physiological concentrations, but little validation has been done in vivo. We utilised CRISPR gene editing to delete all known immune inducible AMPs of Drosophila, namely: 4 Attacins, 4 Cecropins, 2 Diptericins, Drosocin, Drosomycin, Metchnikowin and Defensin. Using individual and multiple knockouts, including flies lacking all 14 AMP genes, we characterize the in vivo function of individual and groups of AMPs against diverse bacterial and fungal pathogens. We found that Drosophila AMPs act primarily against Gram-negative bacteria and fungi, acting either additively or synergistically. We also describe remarkable specificity wherein certain AMPs contribute the bulk of microbicidal activity against specific pathogens, providing functional demonstrations of highly specific AMP-pathogen interactions in an in vivo setting.

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An atypical Phytophthora sojae RxLR effector manipulates host vesicle trafficking to promote infection

PLoS Pathogens ◽

10.1371/journal.ppat.1010104 ◽

2021 ◽

Vol 17 (11) ◽

pp. e1010104

Author(s):

Haonan Wang ◽

Baodian Guo ◽

Bo Yang ◽

Haiyang Li ◽

Yuanpeng Xu ◽

...

Keyword(s):

Vesicle Trafficking ◽

Phytophthora Sojae ◽

Snare Complex ◽

Microbial Pathogens ◽

Rxlr Effector ◽

Pathogenesis Related Protein ◽

Liquid Chromatography Tandem Mass ◽

Related Proteins

In plants, the apoplast is a critical battlefield for plant-microbe interactions. Plants secrete defense-related proteins into the apoplast to ward off the invasion of pathogens. How microbial pathogens overcome plant apoplastic immunity remains largely unknown. In this study, we reported that an atypical RxLR effector PsAvh181 secreted by Phytophthora sojae, inhibits the secretion of plant defense-related apoplastic proteins. PsAvh181 localizes to plant plasma membrane and essential for P. sojae infection. By co-immunoprecipitation assay followed by liquid chromatography-tandem mass spectrometry analyses, we identified the soybean GmSNAP-1 as a candidate host target of PsAvh181. GmSNAP-1 encodes a soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein, which associates with GmNSF of the SNARE complex functioning in vesicle trafficking. PsAvh181 binds to GmSNAP-1 in vivo and in vitro. PsAvh181 interferes with the interaction between GmSNAP-1 and GmNSF, and blocks the secretion of apoplastic defense-related proteins, such as pathogenesis-related protein PR-1 and apoplastic proteases. Taken together, these data show that an atypical P. sojae RxLR effector suppresses host apoplastic immunity by manipulating the host SNARE complex to interfere with host vesicle trafficking pathway.

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Antimicrobial Peptides: Virulence and Resistance Modulation in Gram-Negative Bacteria

Microorganisms ◽

10.3390/microorganisms8020280 ◽

2020 ◽

Vol 8 (2) ◽

pp. 280 ◽

Cited By ~ 1

Author(s):

Marylise Duperthuy

Keyword(s):

Antimicrobial Peptides ◽

Bacterial Resistance ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Low Concentrations ◽

Resistance Modulation ◽

Subinhibitory Concentrations ◽

The Impact

Growing resistance to antibiotics is one of the biggest threats to human health. One of the possibilities to overcome this resistance is to use and develop alternative molecules such as antimicrobial peptides (AMPs). However, an increasing number of studies have shown that bacterial resistance to AMPs does exist. Since AMPs are immunity molecules, it is important to ensure that their potential therapeutic use is not harmful in the long term. Recently, several studies have focused on the adaptation of Gram-negative bacteria to subinhibitory concentrations of AMPs. Such concentrations are commonly found in vivo and in the environment. It is therefore necessary to understand how bacteria detect and respond to low concentrations of AMPs. This review focuses on recent findings regarding the impact of subinhibitory concentrations of AMPs on the modulation of virulence and resistance in Gram-negative bacteria.

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De Novo Design of Potent Antimicrobial Peptides

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.9.3349-3357.2004 ◽

2004 ◽

Vol 48 (9) ◽

pp. 3349-3357 ◽

Cited By ~ 104

Author(s):

V. Frecer ◽

B. Ho ◽

J. L. Ding

Keyword(s):

Antimicrobial Peptides ◽

Rational Design ◽

Lipid A ◽

De Novo ◽

Endotoxic Shock ◽

Antimicrobial Properties ◽

Antimicrobial Effect ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Qsar Analysis

ABSTRACT Lipopolysaccharide (LPS), shed by gram-negative bacteria during infection and antimicrobial therapy, may lead to lethal endotoxic shock syndrome. A rational design strategy based on the presumed mechanism of antibacterial effect was adopted to design cationic antimicrobial peptides capable of binding to LPS through tandemly repeated sequences of alternating cationic and nonpolar residues. The peptides were designed to achieve enhanced antimicrobial potency due to initial bacterial membrane binding with a reduced risk of endotoxic shock. The peptides designed displayed binding affinities to LPS and lipid A (LA) in the low micromolar range and by molecular modeling were predicted to form amphipathic β-hairpin-like structures when they bind to LPS or LA. They also exhibited strong effects against gram-negative bacteria, with MICs in the nanomolar range, and low cytotoxic and hemolytic activities at concentrations significantly exceeding their MICs. Quantitative structure-activity relationship (QSAR) analysis of peptide sequences and their antimicrobial, cytotoxic, and hemolytic activities revealed that site-directed substitutions of residues in the hydrophobic face of the amphipathic peptides with less lipophilic residues selectively decrease the hemolytic effect without significantly affecting the antimicrobial or cytotoxic activity. On the other hand, the antimicrobial effect can be enhanced by substitutions in the polar face with more polar residues, which increase the amphipathicity of the peptide. On the basis of the QSARs, new analogs that have strong antimicrobial effects but that lack hemolytic activity can be proposed. The findings highlight the importance of peptide amphipathicity and allow a rational method that can be used to dissociate the antimicrobial and hemolytic effects of cationic peptides, which have potent antimicrobial properties, to be proposed.

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Virtual Screening to Identify the Protein Targets in Common Dental Pathogens Interacting with Menthol

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2020/v32i2130749 ◽

2020 ◽

pp. 25-31

Author(s):

J. S. Thaslima Nandhini ◽

A. S. Smiline Girija ◽

J. Vijayashree Priyadharsini

Keyword(s):

Antimicrobial Effect ◽

Functional Class ◽

Microbial Pathogens ◽

In Vivo Studies ◽

Protein Targets ◽

Good Target ◽

Study Results ◽

Selection Of

Deducing the molecular pathway underlying the antimicrobial effect of phytocompounds is an inevitable part of drug discovery. Selection of potential targets on the microbial pathogens will eventually lead to eradication of microbes and effective treatment. In this context, the present insilico study identifies vital targets in the dental pathogens interacting with menthol. The STITCHtool was used for identifying the protein drug interaction, VICMPred and VirulentPred tools were used for identifying the functional class and virulence nature of proteins. PSORTb was used to locate the sub-cellular location of the virulent proteins. The study results indicate that menthol interacts with virulence factors of Treponema denticola. These factors play a crucial role in cell survival and hence can be a good target for further in vitro and in vivo studies. To conclude, menthol was found to interact with crucial proteins of dental pathogens which can be targeted to achieve promising results.

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Recent Advances in the Development of Antimicrobial Peptides (AMPs): Attempts for Sustainable Medicine?

Current Medicinal Chemistry ◽

10.2174/0929867325666180117142142 ◽

2018 ◽

Vol 25 (21) ◽

pp. 2503-2519 ◽

Cited By ~ 4

Author(s):

Anne Kokel ◽

Marianna Torok

Keyword(s):

Side Effects ◽

Antimicrobial Peptides ◽

Potential Drug ◽

Green Technologies ◽

Specific Antibodies ◽

Structural Modifications ◽

Drug Candidates ◽

Induce Resistance ◽

Conventional Antibiotics

Background: Since the first isolation of antimicrobial peptides (AMPs) they have attracted extensive interest in medicinal chemistry. However, only a few AMP-based drugs are currently available on the market. Despite their effectiveness, biodegradability, and versatile mode of action that is less likely to induce resistance compared to conventional antibiotics, AMPs suffer from major issues that need to be addressed to broaden their use. Notably, AMPs can lack selectivity leading to side effects and cytotoxicity, and also exhibit in vivo instability. Several strategies are being actively considered to overcome the limitations that restrain the success of AMPs. Methods: In the current work, recent strategies reported for improving AMPs in the context of drug design and delivery were surveyed, and also their possible impact on patients and the environment was assessed. Results: As a major advantage AMPs possess an easily tunable skeleton offering opportunities to improve their properties. Strategic structural modifications and the beneficial properties of cyclic or branched AMPs in term of stability have been reported. The conjugation of AMPs with nanoparticles has also been explored to increase their in vivo stability. Other techniques such as the coupling of AMPs with specific antibodies aim to increase the selectivity of the potential drug towards the target. These strategies were evaluated for their effect on the environment highlighting green technologies. Conclusion: Although further research is needed taking into account both environmental and human health consequences of novel AMPs, several of these compounds are promising drug candidates for use in sustainable medicine.

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