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The Inhibition of DNA Viruses by the Amphibian Antimicrobial Peptide Temporin G: A Virological Study Addressing HSV-1 and JPCyV.

ABSTRACT: Herpes simplex virus type-1 (HSV-1) and John Cunningham polyomavirus (JCPyV) are widely distributed DNA viruses causing mainly asymptomatic infection, but also mild to very severe diseases, especially when these viruses reach the brain. Some drugs have been developed to inhibit HSV-1 replication in host cells, but their prolonged use may induce resistance phenomena. In contrast, to date, there is no cure for JCPyV. The search for alternative drugs that can reduce viral infections without undermining the host cell is moving toward antimicrobial peptides (AMPs) of natural occurrence. These include amphibian AMPs belonging to the temporin family. Herein, we focus on temporin G (TG), showing that it strongly affects HSV-1 replication by acting either during the earliest stages of its life cycle or directly on the virion. Computational studies have revealed the ability of TG to interact with HSV-1 glycoprotein B. We also found that TG reduced JCPyV infection, probably affecting both the earliest phases of its life cycle and the viral particle, likely through an interaction with the viral capsid protein VP1. Overall, our results are promising for the development of short naturally occurring peptides as antiviral agents used to counteract diseases related to HSV-1 and JCPyV.

SUBMITTER: Marcocci ME

PROVIDER: S-EPMC9266403 | biostudies-literature |

REPOSITORIES: biostudies-literature

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New Perspectives in the Antimicrobial Activity of the Amphibian Temporin B: Peptide Analogs Are Effective Inhibitors of <i>Candida albicans</i> Growth.

Project description:Temporin B (TB) is a short, positively charged peptide secreted by the granular glands of the European frog Rana temporaria. While the antibacterial and antiviral efficacy of TB and some of its improved analogs are well documented, nothing is known about their antifungal potency so far. We dedicated this study to characterize the antifungal potential of the TB analog TB_KKG6K and the newly designed D-Lys_TB_KKG6K, the latter having the L-lysines replaced by the chiral counterpart D-lysines to improve its proteolytic stability. Both peptides inhibited the growth of opportunistic human pathogenic yeasts and killed planktonic and sessile cells of the most prevalent human pathogen, Candida albicans. The anti-yeast efficacy of the peptides coincided with the induction of intracellular reactive oxygen species. Their thermal, cation, pH and serum tolerance were similar, while the proteolytic stability of D-Lys_TB_KKG6K was superior to that of its template peptide. Importantly, both peptides lacked hemolytic activity and showed minimal in vitro cytotoxicity in primary human keratinocytes. The tolerance of both peptides in a reconstructed human epidermis model further supports their potential for topical application. Our results open up an exciting field of research for new anti-Candida therapeutic options based on amphibian TB analogs.

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Temporin-SHf, a new type of phe-rich and hydrophobic ultrashort antimicrobial peptide.

Project description:Because issues of cost and bioavailability have hampered the development of gene-encoded antimicrobial peptides to combat infectious diseases, short linear peptides with high microbial cell selectivity have been recently considered as antibiotic substitutes. A new type of short antimicrobial peptide, designated temporin-SHf, was isolated and cloned from the skin of the frog Pelophylax saharica. Temporin-SHf has a highly hydrophobic sequence (FFFLSRIFa) and possesses the highest percentage of Phe residues of any known peptide or protein. Moreover, it is the smallest natural linear antimicrobial peptide found to date, with only eight residues. Despite its small size and hydrophobicity, temporin-SHf has broad-spectrum microbicidal activity against Gram-positive and Gram-negative bacteria and yeasts, with no hemolytic activity. CD and NMR spectroscopy combined with restrained molecular dynamics calculations showed that the peptide adopts a well defined non-amphipathic alpha-helical structure from residue 3 to 8, when bound to zwitterionic dodecyl phosphocholine or anionic SDS micelles. Relaxation enhancement caused by paramagnetic probes showed that the peptide adopts nearly parallel orientations to the micelle surface and that the helical structure is stabilized by a compact hydrophobic core on one face that penetrates into the micelle interior. Differential scanning calorimetry on multilamellar vesicles combined with membrane permeabilization assays on bacterial cells indicated that temporin-SHf disrupts the acyl chain packing of anionic lipid bilayers, thereby triggering local cracks and microbial membrane disintegration through a detergent-like effect probably via the carpet mechanism. The short length, compositional simplicity, and broad-spectrum activity of temporin-SHf make it an attractive candidate to develop new antibiotic agents.

| S-EPMC2878016 | biostudies-literature

The antimicrobial peptide Temporin-L induces vesicle formation and reduces the virulence in S. aureus.

Project description:The evolution of methicillin-resistant Staphylococcus aureus (MRSA) has required the development of new antimicrobial agents and new approaches to prevent and overcome drug resistance. AntiMicrobial Peptides (AMPs) represent promising alternatives due to their rapid bactericidal activity and their broad-spectrum of action against a wide range of microorganisms. The amphibian Temporins constitute a well-known family of AMPs with high antibacterial properties against both Gram-positive and Gram-negative bacteria. In this paper, we evaluated the in vivo effect of Temp-L on S. aureus performing morphological studies using Transmission Electron Microscopy (TEM) that revealed the occurrence of protrusions from the cell surface. The formation of vesicle-like structure was confirmed by Dynamic Light Scattering (DLS). The global effect of Temp-L on Staphylococcus aureus (S. aureus) was deeply investigated by differential proteomics leading to the identification of up-regulated proteins involved in the synthesis of the cell membrane and fatty acids, and down-regulated virulence factors. GC-MS analysis suggested a possible protective response mechanism implemented by the bacterium after treatment with Temp-L, as the synthesis of fatty acids was increased. Adhesion and invasion assays on eukaryotic cells confirmed a reduced virulence of S. aureus following treatment with Temp-L. These results suggested the targeting of virulence factors as novel strategy to replace traditional antimicrobial agents that can be used to treat infections, especially infections caused by the resistant pathogen S. aureus.

| S-EPMC11375239 | biostudies-literature

Inhibition of Escherichia coli ATP synthase by amphibian antimicrobial peptides.

Project description:Previously melittin, the alpha-helical basic honey bee venom peptide, was shown to inhibit F(1)-ATPase by binding at the beta-subunit DELSEED motif of F(1)F(o)-ATP synthase. Herein, we present the inhibitory effects of the basic alpha-helical amphibian antimicrobial peptides, ascaphin-8, aurein 2.2, aurein 2.3, carein 1.8, carein 1.9, citropin 1.1, dermaseptin, maculatin 1.1, maganin II, MRP, or XT-7, on purified F(1) and membrane bound F(1)F(0)Escherichia coli ATP synthase. We found that the extent of inhibition by amphibian peptides is variable. Whereas MRP-amide inhibited ATPase essentially completely (approximately 96% inhibition), carein 1.8 did not inhibit at all (0% inhibition). Inhibition by other peptides was partial with a range of approximately 13-70%. MRP-amide was also the most potent inhibitor on molar scale (IC(50) approximately 3.25 microM). Presence of an amide group at the c-terminal of peptides was found to be critical in exerting potent inhibition of ATP synthase ( approximately 20-40% additional inhibition). Inhibition was fully reversible and found to be identical in both F(1)F(0) membrane preparations as well as in isolated purified F(1). Interestingly, growth of E. coli was abrogated in the presence of ascaphin-8, aurein 2.2, aurein 2.3, citropin 1.1, dermaseptin, magainin II-amide, MRP, MRP-amide, melittin, or melittin-amide but was unaffected in the presence of carein 1.8, carein 1.9, maculatin 1.1, magainin II, or XT-7. Hence inhibition of F(1)-ATPase and E. coli cell growth by amphibian antimicrobial peptides suggests that their antimicrobial/anticancer properties are in part linked to their actions on ATP synthase.

| S-EPMC2834880 | biostudies-literature

Mining Amphibian and Insect Transcriptomes for Antimicrobial Peptide Sequences with rAMPage.

Project description:Antibiotic resistance is a global health crisis increasing in prevalence every day. To combat this crisis, alternative antimicrobial therapeutics are urgently needed. Antimicrobial peptides (AMPs), a family of short defense proteins, are produced naturally by all organisms and hold great potential as effective alternatives to small molecule antibiotics. Here, we present rAMPage, a scalable bioinformatics discovery platform for identifying AMP sequences from RNA sequencing (RNA-seq) datasets. In our study, we demonstrate the utility and scalability of rAMPage, running it on 84 publicly available RNA-seq datasets from 75 amphibian and insect species-species known to have rich AMP repertoires. Across these datasets, we identified 1137 putative AMPs, 1024 of which were deemed novel by a homology search in cataloged AMPs in public databases. We selected 21 peptide sequences from this set for antimicrobial susceptibility testing against Escherichia coli and Staphylococcus aureus and observed that seven of them have high antimicrobial activity. Our study illustrates how in silico methods such as rAMPage can enable the fast and efficient discovery of novel antimicrobial peptides as an effective first step in the strenuous process of antimicrobial drug development.

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Aggregation and Its Influence on the Bioactivities of a Novel Antimicrobial Peptide, Temporin-PF, and Its Analogues.

Project description:Temporin is an antimicrobial peptide (AMP) family discovered in the skin secretion of ranid frog that has become a promising alternative for conventional antibiotic therapy. Herein, a novel temporin peptide, Temporin-PF (TPF), was successfully identified from Pelophylax fukienensis. It exhibited potent activity against Gram-positive bacteria, but no effect on Gram-negative bacteria. Additionally, TPF exhibited aggregation effects in different solutions. Three analogs were further designed to study the relationship between the aggregation patterns and bioactivities, and the MD simulation was performed for revealing the pattern of the peptide assembly. As the results showed, all peptides were able to aggregate in the standard culture media and salt solutions, especially CaCl2 and MgCl2 buffers, where the aggregation was affected by the concentration of the salts. MD simulation reported that all peptides were able to form oligomers. The parent peptide assembly depended on the hydrophobic interaction via the residues in the middle domain of the sequence. However, the substitution of Trp/D-Trp resulted in an enhanced inter-peptide interaction in the zipper-like domain and eliminated overall biological activities. Our study suggested that introducing aromaticity at the zipper-like domain for temporin may not improve the bioactivities, which might be related to the formation of aggregates via the inter-peptide contacts at the zipper-like motif domain, and it could reduce the binding affinity to the lipid membrane of microorganisms.

| S-EPMC8123395 | biostudies-literature

Structurally plastic peptide capsules for synthetic antimicrobial viruses.

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| S-EPMC5633914 | biostudies-literature

Effects of the antimicrobial peptide temporin L on cell morphology, membrane permeability and viability of Escherichia coli.

Project description:Antimicrobial peptides are produced by all organisms in response to microbial invasion and are considered as promising candidates for future antibiotics. There is a wealth of evidence that many of them interact and increase the permeability of bacterial membranes as part of their killing mechanism. However, it is not clear whether this is the lethal step. To address this issue, we studied the interaction of the antimicrobial peptide temporin L with Escherichia coli by using fluorescence, confocal and electron microscopy. The peptide previously isolated from skin secretions of the frog Rana temporaria has the sequence FVQWFSKFLGRIL-NH2. With regard to fluorescence microscopy, we applied, for the first time, a triple-staining method based on the fluorochromes 5-cyano-2,3-ditolyl tetrazolium chloride, 4',6-diamidino-2-phenylindole and FITC. This technique enabled us to identify, in the same sample, both living and total cells, as well as bacteria with altered membrane permeability. These results reveal that temporin L increases the permeability of the bacterial inner membrane in a dose-dependent manner without destroying the cell's integrity. At low peptide concentrations, the inner membrane becomes permeable to small molecules but does not allow the killing of bacteria. However, at high peptide concentrations, larger molecules, but not DNA, leak out, which results in cell death. Very interestingly, in contrast with many antimicrobial peptides, temporin L does not lyse E. coli cells but rather forms ghost-like bacteria, as observed by scanning and transmission electron microscopy. Besides shedding light on the mode of action of temporin L and possibly that of other antimicrobial peptides, the present study demonstrates the advantage of using the triple-fluorescence approach combined with microscopical techniques to explore the mechanism of membrane-active peptides in general.

| S-EPMC1224231 | biostudies-other

Comparative Genomics of Amphibian-like Ranaviruses, Nucleocytoplasmic Large DNA Viruses of Poikilotherms.

Project description:Recent research on genome evolution of large DNA viruses has highlighted a number of incredibly dynamic processes that can facilitate rapid adaptation. The genomes of amphibian-like ranaviruses - double-stranded DNA viruses infecting amphibians, reptiles, and fish (family Iridoviridae) - were examined to assess variation in genome content and evolutionary processes. The viruses studied were closely related, but their genome content varied considerably, with 29 genes identified that were not present in all of the major clades. Twenty-one genes had evidence of recombination, while a virus isolated from a captive reptile appeared to be a mosaic of two divergent parents. Positive selection was also found to be acting on more than a quarter of Ranavirus genes and was found most frequently in the Spanish common midwife toad virus, which has had a severe impact on amphibian host communities. Efforts to resolve the root of this group by inclusion of an outgroup were inconclusive, but a set of core genes were identified, which recovered a well-supported species tree.

| S-EPMC5081246 | biostudies-literature

An amphibian antimicrobial peptide variant expressed in Nicotiana tabacum confers resistance to phytopathogens.

Project description:Esculentin-1 is a 46-residue antimicrobial peptide present in skin secretions of Rana esculenta. It is effective against a wide variety of micro-organisms, including plant pathogens with negligible effects on eukaryotic cells. As a possible approach to enhance plant resistance, a DNA coding for esculentin-1, with the substitution Met-28Leu, was fused at the C-terminal end of the leader sequence of endopolygalacturonase-inhibiting protein, under the control of the cauliflower mosaic virus 35S promoter region, and introduced into Nicotiana tabacum. The antimicrobial peptide was isolated from the intercellular fluids of healthy leaves of transgenic plants, suggesting that it was properly processed, secreted outside cells and accumulated in the intercellular spaces. The morphology of transgenic plants was unaffected. Challenging these plants with bacterial or fungal phytopathogens demonstrated enhanced resistance up to the second generation. Moreover, transgenic plants displayed insecticidal properties.

| S-EPMC1223161 | biostudies-other

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