Melittin, a honeybee venom‑derived antimicrobial peptide, may target methicillin‑resistant Staphylococcus aureus

Choi,Ji Hae; Jang,A Yeung; Lin,Shunmei; Lim,Sangyong; Kim,Dongho; Park,Kyungho; Han,Sang‑Mi; Yeo,Joo‑Hong; Seo,Ho  Seong

doi:10.3892/mmr.2015.4275

Melittin, a honeybee venom‑derived antimicrobial peptide, may target methicillin‑resistant Staphylococcus aureus

Authors:
- Ji Hae Choi
- A Yeung Jang
- Shunmei Lin
- Sangyong Lim
- Dongho Kim
- Kyungho Park
- Sang‑Mi Han
- Joo‑Hong Yeo
- Ho Seong Seo
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Affiliations: Radiation Biotechnology Research Division, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup Si, North Jeolla 580‑185, Republic of Korea, Department of Dermatology, University of California, San Francisco and Northern California Institute for Research and Education, San Francisco, CA 94121, USA, Sericultural and Apicultural Materials Division, National Academy of Agricultural Science, Rural Development Association, Suwon, Gyeonggi-do 441‑100, Republic of Korea
Published online on: September 1, 2015 https://doi.org/10.3892/mmr.2015.4275
Pages: 6483-6490
Copyright: © Choi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Methicillin‑resistant Staphylococcus aureus (MRSA) is difficult to treat using available antibiotic agents. Honeybee venom has been widely used as an oriental treatment for several inflammatory diseases and bacterial infections. The venom contains predominantly biologically active compounds, however, the therapeutic effects of such materials when used to treat MRSA infections have not been investigated extensively. The present study evaluated bee venom and its principal active component, melittin, in terms of their antibacterial activities and in vivo protection against MRSA infections. In vitro, bee venom and melittin exhibited comparable levels of antibacterial activity, which was more marked against MRSA strains, compared with other Gram‑positive bacteria. When MRSA‑infected mice were treated with bee venom or melittin, only the latter animals were successfully rescued from MRSA‑ induced bacteraemia or exhibited recovery from MRSA‑infected skin wounds. Together, the data of the present study demonstrated for the first time, to the best of our knowledge, that melittin may be used as a promising antimicrobial agent to enhance the healing of MRSA‑induced wounds.

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1	Rasigade JP and Vandenesch F: Staphylococcus aureus: A pathogen with still unresolved issues. Infect Genet Evol. 21:510–514. 2014. View Article : Google Scholar
2	Taylor AR: Methicillin-resistant Staphylococcus aureus infections. Prim Care. 40:637–654. 2013. View Article : Google Scholar : PubMed/NCBI
3	Limbago BM, Kallen AJ, Zhu W, Eggers P, McDougal LK and Albrecht VS: Report of the 13th vancomycin-resistant Staphylococcus aureus isolate from the United States. J Clin Microbiol. 52:998–1002. 2014. View Article : Google Scholar :
4	Corey GR: Staphylococcus aureus bloodstream infections: Definitions and treatment. Clin Infect Dis. 48(Suppl 4): S254–S259. 2009. View Article : Google Scholar : PubMed/NCBI
5	Gould IM: VRSA-doomsday superbug or damp squib? Lancet Infect Dis. 10:816–818. 2010. View Article : Google Scholar : PubMed/NCBI
6	Bassetti M, Merelli M, Temperoni C and Astilean A: New antibiotics for bad bugs: Where are we? Ann Clin Microbiol Antimicrob. 12(22)2013. View Article : Google Scholar : PubMed/NCBI
7	Annila I: Bee venom allergy. Clin Exp Allergy. 30:1682–1687. 2000. View Article : Google Scholar : PubMed/NCBI
8	Son DJ, Lee JW, Lee YH, Song HS, Lee CK and Hong JT: Therapeutic application of anti-arthritis, pain-releasing and anti-cancer effects of bee venom and its constituent compounds. Pharmacol Ther. 115:246–270. 2007. View Article : Google Scholar : PubMed/NCBI
9	Kim JY, Lee WR, Kim KH, An HJ, Chang YC, Han SM, Park YY, Pak SC and Park KK: Effects of bee venom against Propionibacterium acnes-induced inflammation in human keratinocytes and monocytes. Int J Mol Med. 35:1651–1656. 2015.PubMed/NCBI
10	Lee H, Lee EJ, Kim H, Lee G, Um EJ, Kim Y, Lee BY and Bae H: Bee venom-associated Th1/Th2 immunoglobulin class switching results in immune tolerance of NZB/W F1 murine lupus nephritis. Am J Nephrol. 34:163–172. 2011. View Article : Google Scholar : PubMed/NCBI
11	Perumal Samy R, Gopalakrishnakone P, Thwin MM, Chow TK, Bow H, Yap EH and Thong TW: Antibacterial activity of snake, scorpion and bee venoms: A comparison with purified venom phospholipase A2 enzymes. J Appl Microbiol. 102:650–659. 2007. View Article : Google Scholar : PubMed/NCBI
12	Gajski G and Garaj-Vrhovac V: Melittin: A lytic peptide with anticancer properties. Environ Toxicol Pharmacol. 36:697–705. 2013. View Article : Google Scholar : PubMed/NCBI
13	Adade CM, Oliveira IR, Pais JA and Souto-Padron T: Melittin peptide kills Trypanosoma cruzi parasites by inducing different cell death pathways. Toxicon. 69:227–239. 2013. View Article : Google Scholar : PubMed/NCBI
14	Jo M, Park MH, Kollipara PS, An BJ, Song HS, Han SB, Kim JH, Song MJ and Hong JT: Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway. Toxicol Appl Pharmacol. 258:72–81. 2012. View Article : Google Scholar
15	Han SM, Lee GG and Park KK: Acute dermal toxicity study of bee venom (Apis mellifera L.) in rats. Toxicol Res. 28:99–102. 2012. View Article : Google Scholar : PubMed/NCBI
16	Han SM, Lee KG, Park KK and Pak SC: Skin sensitization study of bee venom (Apis mellifera L.) in guinea pigs and rats. Cutan Ocul Toxicol. 32:27–30. 2013. View Article : Google Scholar
17	Han SM, Lee GG and Park KK: Skin sensitization study of bee venom (Apis mellifera L.) in guinea pigs. Toxicol Res. 28:1–4. 2012. View Article : Google Scholar : PubMed/NCBI
18	Seo HS, Mu R, Kim BJ, Doran KS and Sullam PM: Binding of glycoprotein Srr1 of Streptococcus agalactiae to fibrinogen promotes attachment to brain endothelium and the eevelopment of meningitis. PLoS Pathog. 8:e10029472012. View Article : Google Scholar
19	Clinical and Laboratory Standards Institute: M100-S16, Performance standards for antimicrobial susceptibility testing; 16th informational supplement. Clinical and Laboratory Standards Institute; Wayne, PA: 2007
20	Ganesh VK, Rivera JJ, Smeds E, Ko YP, Bowden MG, Wann ER, Gurusiddappa S, Fitzgerald JR and Höök M: A structural model of the Staphylococcus aureus ClfA-fibrinogen interaction opens new avenues for the design of anti-staphylococcal therapeutics. PLoS Pathog. 4:e10002262008. View Article : Google Scholar : PubMed/NCBI
21	Bensing BA, Gibson BW and Sullam PM: The Streptococcus gordonii platelet binding protein GspB undergoes glycosylation independently of export. J Bacteriol. 186:638–645. 2004. View Article : Google Scholar : PubMed/NCBI
22	Seo HS, Cartee RT, Pritchard DG and Nahm MH: A new model of pneumococcal lipoteichoic acid structure resolves biochemical, biosynthetic and serologic inconsistencies of the current model. J Bacteriol. 190:2379–2387. 2008. View Article : Google Scholar : PubMed/NCBI
23	Qian Z, Yin Y, Zhang Y, Lu L, Li Y and Jiang Y: Genomic char-acterization of ribitol teichoic acid synthesis in Staphylococcus aureus: Genes, genomic organization and gene duplication. BMC Genomics. 7(74)2006. View Article : Google Scholar
24	Goldrick BA: MRSA, VRE, and VRSA: How do we control them in nursing homes? Am J Nurs. 104:50–51. 2004. View Article : Google Scholar : PubMed/NCBI
25	Hebert C and Weber SG: Common approaches to the control of multidrug-resistant organisms other than methicillin-resistant Staphylococcus aureus (MRSA). Infect Dis Clin North Am. 25:181–200. 2011. View Article : Google Scholar : PubMed/NCBI
26	Todd B: Beyond MRSA: VISA and VRSA: What will ward off these pathogens in health care facilities? Am J Nurs. 106:28–30. 2006. View Article : Google Scholar : PubMed/NCBI
27	Park D, Jung JW, Lee MO, Lee SY, Kim B, Jin HJ, Kim J, Ahn YJ, Lee KW, Song YS, et al: Functional characterization of naturally occurring melittin peptide isoforms in two honey bee species, Apis mellifera and Apis cerana. Peptides. 53:185–193. 2014. View Article : Google Scholar : PubMed/NCBI
28	Palm NW and Medzhitov R: Role of the inflammasome in defense against venoms. Proc Natl Acad Sci USA. 110:1809–1814. 2013. View Article : Google Scholar : PubMed/NCBI
29	Fennell JF, Shipman WH and Cole LJ: Antibacterial action of a bee venom fraction (melittin) against a penicillin-resistant staphylococcus and other microorganisms. USNRDL-TR-67-101. Res Dev Tech Rep. 5:1–13. 1967.
30	Putz T, Ramoner R, Gander H, Rahm A, Bartsch G, Bernardo K, Ramsay S and Thurnher M: Bee venom secretory phospholipase A2 and phosphatidylinositol-homologues cooperatively disrupt membrane integrity, abrogate signal transduction and inhibit proliferation of renal cancer cells. Cancer Immunol Immunother. 56:627–640. 2007. View Article : Google Scholar
31	Carballido JM, Carballido-Perrig N, Schwärzler C and Lametschwandtner G: Regulation of human T helper cell differentiation by antigen-presenting cells: The bee venom phospholipase A2 model. Chem Immunol Allergy. 91:147–158. 2006. View Article : Google Scholar
32	Lapointe S, Brkovic A, Cloutier I, Tanguay JF, Arm JP and Sirois MG: Group V secreted phospholipase A2 contributes to LPS-induced leukocyte recruitment. J Cell Physiol. 224:127–134. 2010.PubMed/NCBI
33	Sitkiewicz I, Stockbauer KE and Musser JM: Secreted bacterial phospholipase A2 enzymes: Better living through phospholipolysis. Trends Microbiol. 15:63–69. 2007. View Article : Google Scholar
34	Hunt CL, Nauseef WM and Weiss JP: Effect of D-alanylation of (lipo) teichoic acids of Staphylococcus aureus on host secretory phospholipase A2 action before and after phagocytosis by human neutrophils. J Immunol. 176:4987–4994. 2006. View Article : Google Scholar : PubMed/NCBI
35	Koprivnjak T, Peschel A, Gelb MH, Liang NS and Weiss JP: Role of charge properties of bacterial envelope in bactericidal action of human group IIA phospholipase A2 against Staphylococcus aureus. J Biol Chem. 277:47636–47644. 2002. View Article : Google Scholar : PubMed/NCBI
36	Fennell JF, Shipman WH and Cole LJ: Antibacterial action of melittin, a polypeptide from bee venom. Proc Soc Exp Biol Med. 127:707–710. 1968. View Article : Google Scholar : PubMed/NCBI
37	Park JH, Kim KH, Lee WR, Han SM and Park KK: Protective effect of melittin on inflammation and apoptosis in acute liver failure. Apoptosis. 17:61–69. 2012. View Article : Google Scholar
38	Park HJ, Lee HJ, Choi MS, Son DJ, Song HS, Song MJ, Lee JM, Han SB, Kim Y and Hong JT: JNK pathway is involved in the inhibition of inflammatory target gene expression and NF-kappaB activation by melittin. J Inflamm (Lond). 5:72008. View Article : Google Scholar
39	Moon DO, Park SY, Choi YH, Kim ND, Lee C and Kim GY: Melittin induces Bcl-2 and caspase-3-dependent apoptosis through downregulation of Akt phosphorylation in human leukemic U937 cells. Toxicon. 51:112–120. 2008. View Article : Google Scholar
40	Sommer A, Fries A, Cornelsen I, Speck N, Koch-Nolte F, Gimpl G, Andrä J, Bhakdi S and Reiss K: Melittin modulates keratinocyte function through P2 receptor-dependent ADAM activation. J Biol Chem. 287:23678–23689. 2012. View Article : Google Scholar : PubMed/NCBI
41	Dempsey CE: The actions of melittin on membranes. Biochim Biophys Acta. 1031:143–161. 1990. View Article : Google Scholar : PubMed/NCBI
42	Kim SJ, Park JH, Kim KH, Lee WR, Kim KS and Park KK: Melittin inhibits atherosclerosis in LPS/high-fat treated mice through athero-protective actions. J Atheroscler Thromb. 18:1117–1126. 2011. View Article : Google Scholar