Clavaspirin, an antibacterial and haemolytic peptide from <i>Styela clava</i>

In, Izzat; Zhao, Chengquan; Nguyen, Tam; Menzel, Lorenzo P.; Waring, Alan J.; Lehrer, Robert I.; Sherman, Mark A.

doi:10.1034/j.1399-3011.2001.10975.x

Cited by 53 publications

(6 citation statements)

References 31 publications

(49 reference statements)

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“…For example, in a study by Rathinakumar et al 31 , sheep and human erythrocytes show different haemolysis levels when exposed to AMPs (0.5, 5 and 15 µM), where sheep erythrocytes prove to be more resistant than human red blood cells 31 . Similar differences in haemolysis between bovine and human blood were reported by Lee et al 32 and Belokoneva and co-workers 30 . These preliminary studies indicate that the differences between mammalian erythrocyte sensitivity towards AMPs can be substantial and that the choice of potentially misleading toxicity controls can easily adversely affect the outcome or conclusions of a study 33 .…”

supporting

confidence: 86%

Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides

Greco

Molchanova

Holmedal

et al. 2020

Sci Rep

265

213

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the use of non-standard toxicity models is a hurdle in the early development of antimicrobial peptides towards clinical applications. Herein we report an extensive in vitro and in vivo toxicity study of a library of 24 peptide-based antimicrobials with narrow spectrum activity towards veterinary pathogens. The haemolytic activity of the compounds was evaluated against four different species and the relative sensitivity against the compounds was highest for canine erythrocytes, intermediate for rat and human cells and lowest for bovine cells. Selected peptides were additionally evaluated against HeLa, HaCaT and HepG2 cells which showed increased stability towards the peptides. Therapeutic indexes of 50-500 suggest significant cellular selectivity in comparison to bacterial cells. Three peptides were administered to rats in intravenous acute dose toxicity studies up to 2-8 × MIC. None of the injected compounds induced any systemic toxic effects in vivo at the concentrations employed illustrating that the correlation between the different assays is not obvious. This work sheds light on the in vitro and in vivo toxicity of this class of promising compounds and provides insights into the relationship between the different toxicity models often employed in different manners to evaluate the toxicity of novel bioactive compounds in general. Antimicrobial peptides (AMPs) have attracted great interest in clinical research over the past three decades as potential therapeutic agents against multidrug resistant bacteria. AMPs are produced by most living organisms and they act as host defense peptides by providing a rapid first line of defense against pathogens 1,2. They come in a variety of sizes and shapes but they are generally cationic and consist of less than 50 amino acids with antimicrobial activities in the low micromolar range 1,3. The discovery that the natural peptides often can be significantly simplified with maintained biological activities makes them plausible candidates for the development of antimicrobials 4-7. Currently, 36 antimicrobial peptides are undergoing preclinical and clinical phase 8 and almost 10,000 papers have been published in 2019 on AMPs. While several natural lipo-and glycopeptides, e.g. colistin and vancomycin, have been approved by the Food and Drug Administration (FDA) as antibiotics, AMPs have yet to make a significant impact on the drug market despite often being heralded as a promising option for the future treatment of drug resistant bacterial and fungal infections 9. AMPs are inherently not metabolically stable and their short half-lives and poor oral bioavailability, combined with potential toxic side effects

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supporting

confidence: 86%

Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides

Greco

Molchanova

Holmedal

et al. 2020

Sci Rep

265

213

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“…In H. roretzi , halocyamines A and B are synthesized by MCs (127), and their cytotoxic activity is likely related to the presence of diphenol rings that render them substrates for PO. S. clava MCs produce clavanins A–D, histidine-rich, α-helix peptides, and clavaspirin (128, 129). In the same species, five styelins, cationic antimicrobial peptides, were identified and isolated from hemocyte lysates (130, 131).…”

Section: Humoral Defensive Repertoirementioning

confidence: 99%

Immunity in Protochordates: The Tunicate Perspective

Franchi

Ballarin

2017

Front. Immunol.

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Tunicates are the closest relatives of vertebrates, and their peculiar phylogenetic position explains the increasing interest toward tunicate immunobiology. They are filter-feeding organisms, and this greatly influences their defense strategies. The majority of the studies on tunicate immunity were carried out in ascidians. The tunic acts as a first barrier against pathogens and parasites. In addition, the oral siphon and the pharynx represent two major, highly vascularized, immune organs, where circulating hemocytes can sense non-self material and trigger immune responses that, usually, lead to inflammation and phagocytosis. Inflammation involves the recruitment of circulating cytotoxic, phenoloxidase (PO)-containing cells in the infected area, where they degranulate as a consequence of non-self recognition and release cytokines, complement factors, and the enzyme PO. The latter, acting on polyphenol substrata, produces cytotoxic quinones, which polymerize to melanin, and reactive oxygen species, which induce oxidative stress. Both the alternative and the lectin pathways of complement activation converge to activate C3: C3a and C3b are involved in the recruitment of hemocytes and in the opsonization of foreign materials, respectively. The interaction of circulating professional phagocytes with potentially pathogenic foreign material can be direct or mediated by opsonins, either complement dependent or complement independent. Together with cytotoxic cells, phagocytes are active in the encapsulation of large materials. Cells involved in immune responses, collectively called immunocytes, represent a large fraction of hemocytes, and the presence of a cross talk between cytotoxic cells and phagocytes, mediated by secreted humoral factors, was reported. Lectins play a pivotal role as pattern-recognition receptors and opsonizing agents. In addition, variable region-containing chitin-binding proteins, identified in the solitary ascidian Ciona intestinalis, control the settlement and colonization of bacteria in the gut.

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“…Clavaspirin, clavanins and styelins were isolated from another solitary tunicate, Styela clava and these pH dependent AMPs were found to be rich in both histidine and phenylalanine residues [68,69]. In general, it was found that clavaspirin and clavanins possessed pH dependent antibacterial and antifungal activity [65,66,67,76] with low pH, enhancing the ability of these AMPs to adopt α-helical structure and permeabilize the membranes of these organisms [68,69]. It appeared that the protonation of histidine residues under low pH conditions promoted the ability of these AMPs to target microbial membranes whilst the presence of their glycine and phenylalanine residues provided them with the conformational flexibility and structural hydrophobicity to facilitate bilayer partitioning [70,71,72,73,74,75].…”

Section: An Overview Of Ph Dependent Peptides and Proteins With Anmentioning

confidence: 99%

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

et al. 2016

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Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations and hydrogel delivery systems. Nonetheless, many pH dependent AMPs and antimicrobial proteins have yet to be fully characterized and these molecules, as a whole, represent an untapped source of novel biologically active agents that could aid fulfillment of the urgent need for alternatives to conventional antibiotics, helping to avert a return to the pre-antibiotic era.

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Clavaspirin, an antibacterial and haemolytic peptide from Styela clava

Cited by 53 publications

References 31 publications

Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides

Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides

Immunity in Protochordates: The Tunicate Perspective

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

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