Mode of Action of Antimicrobial Peptides Identified from Insects
Mode of Action of Antimicrobial Peptides Identified from Insects
Journal of Life Science. 2015. Jun, 25(6): 715-723
Copyright © 2015, Korean Society of Life Science
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Received : April 27, 2015
  • Accepted : June 15, 2015
  • Published : June 30, 2015
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희정, 이
동건, 이

Insects represent the largest class within the animal kingdom in terms of species number. Humans had been utilized insect in the broad area, including food, agriculture, industry, pharmaceuticals and so on. At present, insects are emerging as a leading group for identifying and extracting novel bioactive substances due to enormous number and a high nutritional value. Insects rely on a suite of systemic response to resist infection such as immune cells, hemocytes, activation of enzymes cascades, and antimicrobial peptide/protein. Among the substances, antimicrobial peptides (AMPs) are main components of potent antimircrobial innate defense system into the insect hemolymph. AMPs raise influential candidate as avenue to resolve the development of antibiotic-resistant microbial organism. Insect AMPs are classified into four main classes: cecropins, insect defensins, glycine/proline-rich peptides. Insect AMPs have been purified, over 150. In this review, AMPs derived from several insects were summarized including honey bee, dung beetle, butterfly and longicorn beetle. These peptides almost exhibited potent antimicrobial activities against human microbial pathogens without causing remarkable hemolysis to erythrocytes excluding melittin, and their mode of action(s) are based on disruption of the plasma membrane or fungal apoptosis. Therefore, study of insect AMPs is expected to be useful for designing novel therapeutic antimicrobial applications.
All multicellular organisms possess some kind of inherent molecular or cellular defense system, to fight against pathogen invasion. The innate immune system present in all plants and animals primarily functions as the first line of defense to fight against infection caused by disease producing organisms [4] . Antimicrobial peptides (AMPs) are important components of the innate defense system and are ubiquitously found in a wide variety of organisms, including plants, insects, invertebrates and mammals [13 , 14] . Among them, insects represent the largest class within the animal kingdom in terms of species numbers, including more than one million described species and an equivalent number of species unidentified [13] . Insects depend on a systemic response to combat infection that classified in to two main types. Constitutive defenses always exist and ready to act. The response was relied on insect immune cells, haemocytes, and rapidly activated enzyme cascades to defend against pathogen. Another defense is the induced response which consist mainly antimicrobial peptides. The simultaneous presence of several antimicrobial peptides acting in synergy can provide insects with a more powerful defense against harmful invader such as bacteria, fungi and protozoa [6] . The first insect AMP was isolated from the pupae of Hyalophora cecropia , and to date, 150 AMPs have been identified [56] . A single insect is known to produce about 10-15 peptides, with each peptide exhibiting a different activity spectrum. This review provides an overview on the classification and representation of insect AMPs.
- Classification of insect AMPs
In order to fight against the constant threat of microbial infection, higher organisms produce small, cationic AMPs, which are important components of mammalian innate immune response. Insect AMPs are broadly classified into four major groups: insect defensins, cecropins, and proline-rich/glycine-rich peptides ( Table 1 ).
The classification of insect AMPs by origins
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The classification of insect AMPs by origins
- Insect defensins
Defensins, which form a part of the host’s innate immune system, is an ancient defense strategy used by multicellular organisms, including plants, animals, and even fungi, to control their natural microbial flora and to fight against various microbial pathogens [52 , 53 , 56] . These defensins consist of more than 100 members that display a wide variety of antibacterial, antifungal, insecticidal activities as well as anti-HIV-1 and/or inhibitory activity against tumor cells [9 , 13 , 24 , 25 , 52 , 53] . Insect defensins are mainly active against Gram-positive bacteria, including Micrococcus luteus , Aerococcus viridians , Bacillus megaterium , B. subtilis , B. thuringiensis , and Staphylococcus aureus [56] . Insect defensins kill bacteria by forming channels in the bacterial cytoplasmic membrane. This has been demonstrated using sapecin [49] , which induces microheterogeneity in the bacterial lipid membrane by interacting with cardiolipin, a major phospholipid, thus forming channels responsible for the biological activity [56] . In addition to bactericidal activity, in vitro fungicidal or fungistatic activity against Candida species, including C. glabrata , as well as antifungal activity against filamentous fungi, A. flavus and F. solani , have also been assessed [51] . A previous study on the yeast, C. albicans , suggests that the conserved helical structure of defensins is primarily responsible for its functioning, while other regions may contribute to binding to microorganisms [56] . A recent study has suggested that intracellular signaling pathways play a vital role in tolerance mechanisms of fungal pathogens against insect defensins [44] .
- Cecropins
Cecropins was first identified from the hemolymph of the giant silk moth Hyalophora cecropia as ‘immune proteins’. Cecropin is a well-studied AMP that is synthesized in fat body cells and hemocytes of insects in response to bacterial infection [1 , 35 , 48] . Cecropins are synthesized as secreted proteins and become active only after the removal of signal peptides [56] . All cecropins exhibit significant sequence similarity and particularly comparable number of cationic residues which are considered crucial for its selective binding to the negatively charged bacterial membranes. Cecropins have been predicted to fold into a three dimensional structure consisting of two α-helices connected by a flexible hinge region. The N-terminal region of the helix is amphipathic, whereas the C-terminal region is largely hydrophobic [1] . This helix-forming ability of the cecropins upon membrane contact is responsible for the formation of bacterial membrane pores. Cecropins are potential targets for the production of enormous quantity of synthetic peptides due to their high selectivity, broad spectrum antibacterial activity combined with low cytotoxicity towards mammalian cells [1] . Furthermore, they have been shown to display varying degree of activity against both Gram-positive and Gram-negative bacteria as well as certain fungi, metazoan, and protozoan parasites, including Plasmodium [54 , 56] .
- Proline-rich/Glycine-rich peptide
Proline-rich AMPs are found in various organisms, including insects, mammals, amphibians, crustaceans, and molluscs. They were first reported in honeybees and cattle [46] . Majority of the known proline-rich AMPs have been isolated from various insect species belonging to orders Hymenoptera, Diptera, Hemiptera, and Lepidoptera, and are classified into two major types, namely short-chain and long-chain peptides [46] . The proline-rich peptides and the glycine-rich peptides are predominantly active against Gram-negative bacterial strains [46] . One of the most striking features of insect proline-rich AMPs is their conserved selective activity spectrum directed against Gram-negative bacteria, particularly Enterobacteriaceae, at very low micromolar concentration range. However, at low concentrations, most of the Gram-positive microorganisms remain unaffected [46] . The overall mechanism of action of proline-rich AMPs in insects has been elucidated using peptides such as pyrrhocoricin from the European sap-sucking bug [38] , apidaecin from the honey bee [9] , and drosocin from the fruit fly [24] . In insects, proline-rich AMPs inhibit bacterial protein folding by binding to DnaK, which ultimately leads to bacterial inactivation [5 , 34 , 46] . Unlike active peptides such as insect defensins, and cecropins, which kill microorganisms within minutes through non stereospecific, lytic/ionophoric mechanisms, apiadaecin, and drosocin take several hours to kill bacteria [13] . In addition to proline-rich AMPs, several antibacterial glycine-rich polypeptides have also been isolated from various insect species including Diptera, Lepidoptera, Hymenoptera, Coleoptera and Hemiptera [13] . The antibacterial activity of the glycine-rich peptides including attacins, sarcotoxins, coleoptericin and holotricin-2 like proline-rich AMPs is also restricted to a limited array of Gram-negative bacterial strains [39] . Attacins from H. cecropia has bacteriostatic activity and inhibits directly bacterial outer membrane to increase permeability [3 , 10 , 11 , 56] . Another glycine-rich peptide sarcotoxin II, coleoptericin, diptericin have bactericidal activity [10] .
- AMPs from the insects and its mechanism
- Honey bee
Honey bee venom is a mixture of over 20 compounds, including active peptides such as melittin, apamine [3] , apidaecin [8] , and abaecin [8 , 43] . Among them, melittin is the principal active component (40 to 50%) of bee ( Apis mellifera ) venom and is a powerful lytic peptide [50] . It is shown to exhibit higher efficacy against Gram-negative than Grampositive bacterial strains. Additionally, it has been shown that melittin also exerts marked antiviral as well as anti-fungal activity [33 , 47] . Characteristically, melittin at low concentration, is shown to bind to membrane lipids of erythrocytes, resulting in hemolysis within some seconds [15] . Therefore, at high concentrations, it is considered as the principal active component for strong hemolytic activity [33] . Melittin forms a pore in the cell membrane by perpendicularly inserting itself into lipid by layers in an α-helical confirmation ( Fig. 1 ) [16 , 33 , 39 , 55] . Therefore, analogues such as leucine zipper motif with lower cytotoxicity towards mammalian cells and simultaneous non-selective activity is useful in melittin studies [40 , 58]. In general, leucine zipper motif is used as a control peptide since it exhibits definite disruption of lipid membrane [33] . Using Annexin V, DAPI, and TUNEL staining, Park et al . [41] confirmed diagnostic markers of apoptosis in C. albicans when exposed to melittin. Consecutively, Lee et al . [33] further characterized the intracellular mechanism of melittin-induced apoptosis in C. albicans [33] further studied in details the intracellular mechanism underlying melittin-induced apoptosis in C. albicans . They suggested that melittin exerted its antifungal activity via apoptosis by increasing reactive oxygen species (ROS) production particularly hydroxyl (OH). They further reported that upon melittin exposure mitochondrial Ca 2+ levels increases to a large extent, suggesting the mitochondrial perturbation or rupture by the decreased mitochondrial membrane potential ( Fig. 1 ) [33] . In addition, melittin is also shown to suppress human immunodeficiency virus-1 (HIV-1) replication by interfering with host-cell directed viral gene expression at different dose concentrations. This suggests that the innate immune system includes an antiviral pathway for rapid defense against virus spread and replication [47] .
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(A) Melittin crystallographic structure [8]. (B) the interactions of melittin with the bacterial cytoplasmic membrane. [42]. (C) Phosphatidylserine externalization shown by FITC-annexin V staining in Melittin-treated C. albicans cells. Melittin (c and d), H2O2 (e and f) or not treated (a and b). Subpanels (a, c, and e) are phase-contrast micrographs. (D) DNA and nuclear fragmentation shown by TUNEL and DAPI staining in Melittin-treated cells. Melittin (a and d), H2O2 (b and e) or not treated. (E) Melittin-treated C. albicans showing apoptotic markers. Annexin+, TUNEL+, and ROS+ refer to the percentage of stained cells [41].
- Dung beetle
Coprisin is a 43-mer defensin-like peptide, which was isolated from the dung beetle, Copris tripartitus in 2009. It has three disulfide bonds at positions 3-34, 20-39 and 24-41 ( Fig. 2A ) [31 , 56] . Since C. tipartitus spends most of its life in fecal material, it is considered that the antibacterial properties of coprisin protect this insect from continuous pathogen invasion [28] . Coprisin exhibits broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria such as Escherichia coli , Salmonella typhimurium , Pseudomonas aeruginosa , Staphylococcus aureus , and S. epidermidis [28] as well as antifungal activity against various fungal pathogens including several species from Aspergillus and Candida genus without any cytotoxicity towards human erythrocytes [30] . Coprisin possesses antibacterial properties and synergistic activities with antibiotics. Coprisin alone and in combi-nation with antibiotics generate hydroxyl radicals, which are highly reactive oxygen forms and important regulators of bactericidal and antibiofilm activity [20] . In fungal cells, several membrane studies suggest that coprisin does not disrupt either cell plasma membrane of C. albicans or fungal model membranes [31] . On the other hand, some diagnostic markers of apoptosis such as phosphatidylserine externalization during early apoptosis and consecutively DNA fragmentation in late apoptosis were examined. The results confirmed that corpisin significantly induce apoptosis in C. albicans [31] . Coprisin additionally caused mitochondrial dysfunction and cytochrome c release/caspase activation as downstream events ( Fig. 2 ) [31] . Additionally, coprisin also exhibits anti-inflammatory activity by suppressing binding of lipolysaccharides (LPS) to toll-like receptor 4, and subsequently inhibiting the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear translocation of Nuclear factor-kB (NF-kB) [27] . Coprisin exerts antibacterial effect when topically applied in both liquid and ointment bases to S. aureus -infected wounds in rats resulting in accelerated wound healing [30] .
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(A) Solution structure of coprisin. The three disulfide bridges are shown in yellow [31]. (B) Confocal laser scanning microscopy of C. albicans cells treated with FITC-labeled coprisin. (a) Negative control under visible light, (b) cells treated with FITC-labeled coprisin and (c) cells treated with nuclear-staining dye. [30] (C) Phosphatidylserine externalization in C. albicans protoplasts induced by (a) negative (b-c) coprisin (1x, 2x, represitively) [30].
- Swallowtail butterfly
Papiliocin is a novel 37-residue cecropin-like AMP, isolated by Kim et al . from the swallowtail butterfly, Papilio xuthus [23 , 26] . It exhibits both potent anti-inflammatory activity [26] and antimicrobial activities against both Gram-positive and Gram-negative bacteria as well as fungi without cytotoxicity against human erythrocytes [23] . Two residues (Trp 2 and Phe 5 ) at the end terminal helix of papiliocin play a vital role in attracting it to the cell membrane of Gram-negative bacteria [56] . Papiliocin is a potent peptide antibiotic suitable for treating endotoxin shock and sepsis caused by Gram-negative bacterial infections [22] . A study on anti-fungal mechanism of paliliocin against C. albicans showed that papiliocin effectively perturbed the fungal plasma membrane by forming pores on the model membrane mimicking the outer leaflets of C. albicans within minutes [29] . Papiliocin formed pores on the model membrane mimicking the outer leaflets of the C. albicans within minutes [29] . Hwang et al. suggested that ROS accumulation and mitochondrial membrane damage are responsible for papiliocin-induced fungal apoptosis ( Fig. 3C ) [17] . They also examined novel antimicrobial mechanism of papiliocin in C. albicans and noted several apoptotic events, such as phosphatidylserine flip-flop, chromatin condensation and DNA fragmentation ( Fig. 3D ) [17] . Although the exact mechanism is still unclear, it will enable effective clinical approaches in treating human fungal disease.
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(A) Ribbon diagram of the lowest structures of (C) papiliocin [26]. (B) Confocal microscopy of C. albicans treated with FITC-labeled papiliocin [29]. (C) ROS generation by papilocin and H2O2 [29]. (D) DNA and nuclear fragmentation shown by DAPI and TUNEL staining [17].
- Longicorn beetle
Longicorn beetile belonging to the insect family Cerambycidae of the insect order Coleoptera is a pest of mulverry and fig tree in East Asia [37] . Psacotheasin have been derived from larvae of the yellow-spotted longicorned beetle, Pscothea hilaris using cDNA encoding. The primary structure is characterized by a knottin-like cysteine motif and exerted potent activities against both Gram-positive and Gram-negative bacterial strains [21] . The peptide exerts an antifungal activity without inducing hemolysis [18] . Although mode of action(s) against bacteria strains was remained unknown, the mechanisms in C. albicans were reported. Psacotheasin which exerts a potent antifungal activity by pore formation in the membrane eventually lead to fungal cell death [18] . Moreover, ROS accumulation, specifically hydroxyl radicals, triggers mitochondrial depolarization. Co-staining of annexin V-fluorescein isothiocyanate (FITC) and propidium iodide, and TUNEL and 4',6-diamidino-2-phenylindole (DAPI) assays exhibited that ROS-induced fungal cell death is associated with apoptosis. Finally, intracellular metacaspase, evidence of hallmark apoptosis, was activated. This corroborated that the antifungal activity against C. albicans is exerted by dual mechanisms which apoptotic mechanism and membrane active mechanism [19] . Overall, the above studies suggest that AMPs from centipede could emerge as a model molecule, which targets the cytoplasmic membrane or apoptotic pathway and provides a novel remedy.
In this review, we provide a complete overview of various kinds of insect AMPs and their underlying molecular mechanism to fight against bacterial and fungal infection ( Fig. 4 , 5 ). While insect AMPs are recognized to have novel therapeutic applications as alternatives of conventional antibiotics, more in-depth studies are required to develop and optimize these peptides as potential anti-infective drugs.
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The mode of actions of insect AMPs in bacteria.
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The mode of actions of insect AMPs in yeast.
This work was supported by a grant from the NextGeneration BioGreen 21 Program (Project No. PJ01104303), Rural Development Administration, Republic of Korea.
Andrä J. , Berninghausen O. , Leippe M. 2001 Cecropins, antibacterial peptides from insects and mammals, are potently fungicidal against Candida albicans Med. Microbiol. Immunol. 189 169 - 173    DOI : 10.1007/s430-001-8025-x
Andres E. , Dimarcg L. 2007 Cationic antimicrobial peptides: from innate immunity study to drug development Med. Mal. Infect. 37 194 - 199    DOI : 10.1016/j.medmal.2006.09.009
Axén A. , Carlsson A. , Engström A. , Bennich H. 1997 Gloverin, an antibacterial protein from the immune hemolymph of Hyalophora pupae Eur. J. Biochem. 247 614 - 619    DOI : 10.1111/j.1432-1033.1997.00614.x
Boman H. G. 2000 Innate immunity and the normal microflora Immunol. Rev. 173 5 - 16    DOI : 10.1034/j.1600-065X.2000.917301.x
Bulet P. , Dimarcq J. L. , Hetru C. , Lagueux M. , Charlet M. , Hegy G. , Van Dorsselaer A. , Hoffmann J. A. 1993 A novel inducible antibacterial peptide of Drosophila carries an O-glycosylated substitution J. Biol. Chem. 268 14893 - 14897
Bulet P. , Hetru C. , Dimarcq J. L. , Hoffmann D. 1999 Antimicrobial peptides in insects; structure and function Dev. Comp. Immunol. 23 156 - 164
Casteels P. , Ampe C. , Jacobs F. , Vaeck M. , Tempst P. 1989 Apidaecins: antibacterial peptides from honeybees EMBO J. 8 2387 - 2391
Casteels P. , Ampe C. , Riviere L. , Van Damme J. , Elicone C. , Fleming M. , Jacobs F. , Tempst P. 1990 Isolation and characterization of abaecin, a major antibacterial response peptide in the honeybee (Apis mellifera) Eur. J. Biochem. 187 381 - 386    DOI : 10.1111/j.1432-1033.1990.tb15315.x
Chen G. H. , Hsu M. P. , Tan C. H. , Sung H. Y. , Kuo C. G. , Fan M. J. , Chen H. M. , Chen S. , Chen C. S. 2005 Cloning and characterization of a plant defensin VaD1 from azuki bean J. Agric. Food Chem. 53 982 - 988    DOI : 10.1021/jf0402227
Cociancich S. , Bulet P. , Hetru C. , Hoffmann J. A. 1994 The inducible antibacterial peptides of insects Parasitol. Today 10 132 - 139    DOI : 10.1016/0169-4758(94)90260-7
Engstrom P. , Carlsson A. , Engstrom A. , Tao J. Z. , Bennich H. 1984 The antibacterial effect of attacins from the silk moth Hyalophora cecropia is directed against the outer membrane of Escherichia coli EMBO J. 3 3347 - 3351
Fujiwara S. , Imai J. , Fujiwara M. , Yaeshima T. , Kawashima T. , Kobayashi K. 1990 A potent antibacterial protein in royal jelly. Purification and determination of the primary structure of royalisin J. Biol. Chem. 265 11333 - 11337
Haine E. R. , Moret Y. , Siva-Jothy M. T. , Rolff J. 2008 Antimicrobial defense and persistent infection in insects Science 21 1257 - 1259
Hancock R. E. 2001 Cationic peptides: effectors in innate immunity and novel antimicrobials Lancet. Infect. Dis. 1 156 - 164    DOI : 10.1016/S1473-3099(01)00092-5
Hider R. C. , Khader F. , Tatham A. S. 1983 Lytic activity of monomeric and oligomeric melittin Biochim. Biophys. Acta. 728 206 - 214    DOI : 10.1016/0005-2736(83)90473-X
Hristova K. , Dempsey C. E. , White S. H. 2001 Structure, location, and lipid perturbations of melittin at the membrane interface Biophys. J. 80 801 - 811    DOI : 10.1016/S0006-3495(01)76059-6
Hwang B. , Hwang J. S. , Lee J. , Kim J. K. , Kim S. R. , Kim Y. , Lee D. G. 2011 Induction of yeast apoptosis by an antimicrobial peptide, Papiliocin Biochem. Biophys. Res. Commun. 408 89 - 93    DOI : 10.1016/j.bbrc.2011.03.125
Hwang B. , Hwang J. S. , Lee J. , Lee D. G. 2010 Antifungal properties and mode of action of psacotheasin, a novel knottin-type peptide derived from Psacothea hilaris Biochem. Biophys. Res. Commun. 400 352 - 357    DOI : 10.1016/j.bbrc.2010.08.063
Hwang B. , Hwang J. S. , Lee J. , Lee D. G. 2011 The antifungal peptide, psacotheasin induces reactive oxygen species and triggers apoptosis in Candida albicans Biochem. Biophys. Res. Commun. 405 267 - 271    DOI : 10.1016/j.bbrc.2011.01.026
Hwang I. S. , Hwang J. S. , Hwang J. H. , Choi H. , Lee E. , Kim Y. , Lee D. G. 2013 Synergistic effect and antibiofilm activity between the antimicrobial peptide coprisin and conventional antibiotics against opportunistic bacteria Curr. Microbiol. 66 46 - 60
Hwang J. S. , Lee J. , Hwang B. , Nam S. H. , Yun E. Y. , Kim S. R. , Lee D. G. 2010 Isolation and characterization of Psacotheasin, a novel Knottin-type antimicrobial peptide, from Psacothea hilaris J. Microbiol. Biotechnol. 20 708 - 711    DOI : 10.4014/jmb.1002.02003
Kim J. K. , Lee E. , Shin S. , Jeong K. W. , Lee J. Y. , Bae S. Y. , Kim S. H. , Lee J. , Kim S. R. , Lee D. G. , Hwang J. S. , Kim Y. 2011 Structure and function of papiliocin with antimicrobial and anti-inflammatory activities isolated from the swallowtail butterfly, Papilio xuthus J. Biol. Chem. 286 41296 - 41311    DOI : 10.1074/jbc.M111.269225
Kim S. R. , Hong M. Y. , Park S. W. , Choi K. H. , Yun E. Y. , Goo T. W. , Kang S. W. , Suh H. J. , Kim I. , Hwang J. S. 2010 Characterization and cDNA cloning of a cecropin-like antimicrobial peptide, papiliocin, from the swallow-tail butterfly, Papilio xuthus Mol. Cells. 29 419 - 423    DOI : 10.1007/s10059-010-0050-y
Landon C. , Sodano P. , Hetru C. , Hoffmann J. , Ptak M. 1997 Solution structure of drosomycin, the first inducible antifungal protein from insects Protein. Sci. 6 1878 - 1884    DOI : 10.1002/pro.5560060908
Lay F. T. , Anderson M. A. 2005 Defensins-components of the innate immune system in plants Curr. Protein Pept. Sci. 6 85 - 101    DOI : 10.2174/1389203053027575
Lee E. , Jeong K. W. , Lee J. , Shin A. , Kim J. K. , Lee J. , Lee D. G. , Kim Y. 2013 Structure-activity relationships of cecropin-like peptides and their interactions with phospholipid membrane BMB Rep. 46 282 - 287    DOI : 10.5483/BMBRep.2013.46.5.252
Lee E. , Shin A. , Kim Y. 2015 Anti-inflammatory activities of cecropin A and its mechanism of action Arch. Insect. Biochem. Physiol. 88 31 - 44    DOI : 10.1002/arch.21193
Lee J. , Han S. Y. , Ji A. R. , Park J. K. , Hong I. H. , Ki M. R. , Lee E. M. , Kim A. Y. , Lee E. J. , Hwang J. S. , Lee J. , Lee D. G. , Jeong K. S. 2013 Antimicrobial effects of coprisin on wounds infected with Staphylococcus aureus in rats Wound. Repair. Regen. 21 876 - 882    DOI : 10.1111/wrr.12112
Lee J. , Hwang J. S. , Hwang B. , Kim J. K. , Kim S. R. , Kim Y. , Lee D. G. 2010 Influence of the papiliocin peptide derived from Papilio xuthus on the perturbation of fungal cell membranes FEMS Microbiol. Lett. 311 70 - 75    DOI : 10.1111/j.1574-6968.2010.02073.x
Lee J. , Hwang J. S. , Hwang I. S. , Cho J. , Lee E. , Kim Y. , Lee D. G. 2012 Coprisin-induced antifungal effects in Candida albicans correlate with apoptotic mechanisms Free Radic. Biol. Med. 52 2302 - 2311    DOI : 10.1016/j.freeradbiomed.2012.03.012
Lee J. , Lee D. , Choi H. , Kim H. H. , Kim H. , Hwang J. S. , Lee D. G. , Kim J. I. 2014 Structure-activity relationships of the intramolecular disulfide bonds in coprisin, a defensin from the dung beetle BMB Rep. 47 625 - 630    DOI : 10.5483/BMBRep.2014.47.11.262
Lee J. , Lee D. G. 2014 Melittin triggers in Candida albicans through the reactive oxygen species-mediated mitochondria/caspase -dependent pathway FEMS Microbiol. Lett. 355 36 - 42    DOI : 10.1111/1574-6968.12450
Lee M. T. , Hung W. C. , Chen F. Y. , Huang H. W. 2008 Mechanism and kinetics of pore formation in membranes by water-soluble amphipathic peptides Proc. Natl. Acad. Sci. USA 105 5087 - 5092    DOI : 10.1073/pnas.0710625105
Lele D. S. , Talat S. , Kumari S. , Srivastava N. , Kaur K. J. 2015 Understanding the importance of glycosylated threonine and stereospecific action of Drosocin, a Proline rich antimicrobial peptide Eur. J. Med. Chem. 92 637 - 647    DOI : 10.1016/j.ejmech.2015.01.032
Liang Y. , Wang J. X. , Zhao X. F. , Du X. J. , Xue J. F. 2006 Molecular cloning and characterization of cecropin from the housefly (Musca domestica), and its expression in Escherichia coli Dev. Comp. Immunol. 30 249 - 257    DOI : 10.1016/j.dci.2005.04.005
Mygind P. H. , Fischer R. L. , Schnorr K. M. , Hansen M. T. , Sönksen C. P. , Ludvigsen S. , Raventós D. , Buskov S. , Christensen B. , De Maria L. , Taboureau O. , Yaver D. , Elvig-Jørgensen S. G. , Sørensen M. V. , Christensen B. E. , Kjaerulff S. , Frimodt-Moller N. , Lehrer R. I. , Zasloff M. , Kristensen H. H. 2005 Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus Nature 437 975 - 980    DOI : 10.1038/nature04051
Nagamine K. , Kayukawa T. , Hoshizaki S. , Matsuo T. , Shinoda T. , Ishikawa Y. 2014 Cloning, phylogeny, and expression analysis of the Broad-Complex gene in the longicorn beetle Psacothea hilaris Springerlpus 5 539 -
Narayanan S. , Modak J. K. , Ryan C. S. , Garcia-Bustos J. , Davies J. K. , Roujeinikova A. 2014 Mechanism of Escherichia coli resistance to Pyrrhocoricin Antimicrob. Agents. Chemother. 58 2754 - 2762    DOI : 10.1128/AAC.02565-13
Otvos L. 2000 Antibacterial peptides isolated from insects J. Pept. Sci. 6 497 - 511    DOI : 10.1002/1099-1387(200010)6:10<497::AID-PSC277>3.0.CO;2-W
Pandey B. K. , Ahmad A. , Asthana N. , Azmi S. , Srivastava R. M. , Srivastava S. , Verma R. , Vishwakarma A. L. , Ghosh J. K. 2010 Cell-selective lysis by novel analogues of melittin against human red blood cells and Escherichia coli Biochemistry 49 7920 - 7929    DOI : 10.1021/bi100729m
Park C. , Lee D. G. 2010 Melittin induces apoptotic features in Candida albicans Biochem. Biophys. Res. Commun. 394 170 - 172    DOI : 10.1016/j.bbrc.2010.02.138
Park S. C. , Kim J. Y. , Shin S. O. , Jeong C. Y. , Kim M. H. , Shin S. Y. , Cheong G. W. , Park Y. , Hahm K. S. 2006 Investigation of toroidal pore and oligomerization by melittin using transmission electron microscopy Biochem. Biophys. Res. Commun. 343 222 - 228    DOI : 10.1016/j.bbrc.2006.02.090
Rahnamaeian M. , Cytryńska M. , Zdybicka-Barabas A. , Dobslaff K. , Wiesner J. , Twyman R. M. , Zuchner T. , Sadd B. M. , Regoes R. R. , Schmid-Hempel P. , Vilcinskas A. 2015 Insect antimicrobial peptides show potentiating functional interactions against Gram-negative bacteria Proc. Biol. Sci. 282 1806 -
Ramamoorthy V. , Zhao X. , Snyder A. K. , Xu J. R. , Shah D. M. 2007 Two mitogen-activated protein kinase signalling cascades mediate basal resistance to antifungal plant defensins in Fusarium graminearum Cell. Microbiol. 9 1491 - 1506    DOI : 10.1111/j.1462-5822.2006.00887.x
Samakovlis C. , Kylsten P. , Kimbrell D. A. , Engström A. , Hultmark D. 1991 The andropin gene and its product, a male-specific antibacterial peptide in Drosophila melanogaster EMBO J. 10 163 - 169
Scocchi M. , Tossi A. , Gennaro R. 2011 Proline-rich antimicrobialpeptides: converging to a non-lytic mechanism of action Cell. Mol. Life. Sci. 68 2317 - 2330    DOI : 10.1007/s00018-011-0721-7
Slocinska M. , Marciniak P. , Rosinski G. 2008 Insects antiviral and anticancer peptides: new leads for the future? Protein. Pept. Lett. 15 578 - 585    DOI : 10.2174/092986608784966912
Steiner H. , Hultmark D. , Engström A. , Bennich H. , Boman H. G. 1981 Sequence and specificity of two antibacterial proteins involved in insect immunity Nature 292 246 - 248    DOI : 10.1038/292246a0
Takeuchi K. , Takahashi H. , Sugai M. , Iwai H. , Kohno T. , Sekimizu K. , Natori S. , Shimada I. 2004 Channel-forming membrane permeabilization by an antibacterial protein, sapecin: determination of membrane-buried and oligomerization surfaces by NMR J. Biol. Chem. 279 4981 - 4987
Terra R. M. , Guimarães J. A. , Verli H. 2007 Structural and functional behavior of biologically active monomeric melittin J. Mol. Graph. Model. 25 767 - 772    DOI : 10.1016/j.jmgm.2006.06.006
Thevissen K. , Kristensen H. H. , Thomma B. P. , Cammue B. P. , François I. E. 2007 Therapeutic potential of antifungal plant and insect defensins Drug. Discov. Today 12 966 - 971    DOI : 10.1016/j.drudis.2007.07.016
Thomma B. P. , Cammue B. P. , Thevissen K. 2002 Plant defensins Planta 216 193 - 202    DOI : 10.1007/s00425-002-0902-6
Thomma B. P. , Cammue B. P. , Thevissen K. 2003 Mode of action of plant defensins suggests therapeutic potential Curr. Drug. Targets. Infect. Disord. 3 1 - 8
Vizioli J. , Bulet P. , Charlet M. , Lowenberger C. , Blass C. , Müller H. M. , Dimopoulos G. , Hoffmann J. , Richman A. 2000 Cloning and analysis of a cecropin gene from the malaria vector mosquito, Anopheles gambiae Insect. Mol. Biol. 9 75 - 84    DOI : 10.1046/j.1365-2583.2000.00164.x
Yang L. , Harroun T. A. , Weiss T. M. , Ding L. , Huang H. W. 2001 Barrel-stave model or toroidal model? A case study on melittin pores Biophys. J. 8 1475 - 1485
Yi H. Y. , Chowdhury M. , Huang Y. D. , Yu X. Q. 2014 Insect antimicrobial peptides and their applications Appl. Microbiol. Biotechnol. 98 5807 - 5822    DOI : 10.1007/s00253-014-5792-6
Zhu W. L. , Song Y. M. , Park Y. , Park T. H. , Yang S. T. , Kim J. I. , Park I. S. , Hahm K. S. , Shin S. Y. 2007 Substitution of the leucine zipper sequence in melittin with peptoid residues affects self-association, cell selectivity, and mode of action Biochim. Biophys. Acta. 1768 1506 - 1517    DOI : 10.1016/j.bbamem.2007.03.010