Hamdan Medical Journal (previously the Journal of Medical Sciences)

Table of Contents  

Clinical Applications of Amphibian Antimicrobial Peptides

J. Michael Conlon, Agnes Sonnevend
Published in : Journal of Medical Sciences ; Vol 4, No 2 (2011)
DOI : 10.2174/1996327001104020062


Frog skin constitutes a rich source of peptides with broad spectrum antimicrobial activity against strains of antibiotic-resistant bacteria and fungi and several hundred such peptides from diverse species have been described. However, their therapeutic potential remains to be realized and no anti-infective peptide based upon their structures has yet been adopted in clinical practice. This review assesses potential clinical applications of nine antimicrobial peptides isolated from frog skin (alyteserin-1c, ascaphin-8, brevinin-1BYa, brevinin-2PRa, brevinin-2-related peptide, brevinin-2- related peptide-ERa, kassinatuerin-1, pseudin-2, and temporin-DRa). The multidrug-resistant microorganisms targeted include the Gram-negative bacteria Acinetobacter baumannii, Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa, the Gram-positive bacterium Staphylococcus aureus, and the opportunistic yeast pathogens Candida spp. Although the naturally occurring peptides show varying degrees of cytotoxicity towards mammalian cells such as erythrocytes, analogs have been developed that retain high antimicrobial potency but are nonhemolytic. Treatment and prevention of acne and periodontal disease are identified as areas in which frog skin antimicrobial peptides might find future applications.


Frog skin; antimicrobial peptide; antibiotic-resistant bacteria

View article in  :   PDF    


Norrby SR, Nord CE, Finch R. Lack of development of new antimicrobial drugs: a potential serious threat to public health. Lancet Infect Dis 2005; 5: 115-9.

Livermore DM. Has the era of untreatable infections arrived? J Antimicrob Chemother 2009; 64 Suppl 1: i29-36.

Diamond G, Beckloff N, Weinberg A, Kisich KO. The roles of antimicrobial peptides in innate host defense. Curr Pharm Des 2009; 15: 2377-92.

Zaiou M. Multifunctional antimicrobial peptides: therapeutic targets in several human diseases. J Mol Med 2007; 85: 317-29.

Perron GG, Zasloff M, Bell G. Experimental evolution of resistance to an antimicrobial peptide. Proc Biol Sci 2006; 273: 251-6.

Zasloff M. Antimicrobial peptides in health and disease. N Engl J Med 2002; 347: 1199-200.

Rinaldi AC. Antimicrobial peptides from amphibian skin: an expanding scenario. Curr Opin Chem Biol 2002; 6: 799-804.

Conlon JM. The contribution of skin antimicrobial peptides to the system of innate immunity in anurans. Cell Tissue Res 2011; 343: 201-12.

Zasloff M. Magainins, a class of antimicrobial peptides from Xenopus skin: isolation, characterization of two active forms and partial cDNA sequence of a precursor. Proc Natl Acad Sci USA 1987; 84: 5449-53.

Giovannini MG, Poulter L, Gibson BW, Williams DH. Biosynthesis and degradation of peptides derived from Xenopuslaevispro hormones. Biochem J 1987; 243: 113-20.

Abbassi F, Lequin O, Piesse C, Goasdoué N, Foulon T, Nicolas P, et al. Temporin-SHf, a new type of Pherich and hydrophobic ultrashort antimicrobial peptide. J Biol Chem 2010; 285: 16880-92.

Powers JP, Hancock RE. The relationship between peptide structure and antibacterial activity. Peptides 2003; 24: 1681-91.

Yeaman MR, Yount NY. Mechanisms of antimicrobial peptide action and resistance. Pharmacol Rev 2003; 55: 27-55.

Conlon JM, Kolodziejek J, Nowotny N. Antimicrobial peptides from the skins of North American frogs. Biochim Biophys Acta 2009; 1788: 1556-63.

Tennessen JA, Woodhams DC, Chaurand P, Reinert LK, Billheimer D, Shyr Y, et al. Variations in the expressed antimicrobial peptide repertoire of northern leopard frog (Ranapipiens) populations suggest intraspecies differences in resistance to pathogens. Dev Comp Immunol 2009; 33: 1247-57.

Lowy FD. Staphylococcus aureus infections. N Engl J Med 1998; 339: 520-32.

Zetola N, Francis JS, Nuermberger EL, Bishai WR. Community-acquired meticillin-resistant Staphylococcus aureus: an emerging threat. Lancet Infect Dis 2005; 5: 275-86.

Woodford N, Livermore DM. Infections caused by Gram-positive bacteria: a review of the global challenge. J Infect 2009; 59 Suppl 1: S4-16.

Conlon JM, Al-Ghaferi N, Coquet L, Leprince J, Jouenne T, Vaudry H, et al. Evidence from peptidomic analysis of skin secretions that the redlegged frogs, Rana aurora draytonii and Rana aurora aurora, are distinct species. Peptides 2006; 27: 1305-12.

Conlon JM, Al-Ghaferi N, Abraham B, Leprince J. Strategies for transformation of naturally-occurring amphibian antimicrobial peptides into therapeutically valuable anti-infective agents. Methods 2007; 42: 349-57.

Dathe M, Wieprecht T, Nikolenko H, Handel L, Maloy WL, MacDonald DL, et al. Hydrophobicity, hydrophobic moment and angle subtended by charged residues modulate antibacterial and haemolytic activity of amphipathic helical peptides. FEBS Lett 1997; 403: 208-12.

Al-Ghaferi N, Kolodziejek J, Nowotny N, Coquet L, Jouenne T, Leprince J, et al. Antimicrobial peptides from the skin secretions of the South-East Asian frog Hylaranaerythraea (Ranidae). Peptides 2010; 31: 548-54.

Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev 2005; 18: 657-86.

Pitout JD. Infections with extended-spectrum betalactamase- producing enterobacter iaceae: changing epidemiology and drug treatment choices. Drugs 2010; 70: 313-33.

Livermore DM, Canton R, Gniadkowski M, Nordmann P, Rossolini GM, Arlet G, et al. CTX-M: changing the face of ESBLs in Europe. J Antimicrob Chemother 2007; 59: 165-74.

Conlon JM, Sonnevend A, Davidson C, Smith DD, Nielsen PF. The ascaphins: a family of antimicrobial peptides from the skin secretions of the most primitive extant frog, Ascaphustruei. Biochem Biophys Res Commun 2004; 320: 170-5.

Eley A, Ibrahim M, Kurdi SE, Conlon JM. Activities of the frog skin peptide, ascaphin-8 and its lysinesubstituted analogs against clinical isolates of extended-spectrum beta-lactamase (ESBL) producing bacteria. Peptides 2008; 29: 25-30.

Olson L, Soto A, Knoop FC, Conlon JM. Pseudin-2: an antimicrobial peptide with low hemolytic activity from the skin of the paradoxical frog. Biochem Biophys Res Commun 2001; 288: 1001-5.

Pál T, Sonnevend A, Galadari S, Conlon JM. Design of potent, non-toxic antimicrobial agents based upon the structure of the frog skin peptide, pseudin-2. Regul Pept 2005; 129: 85-91.

Matutte B, Knoop FC, Conlon JM. Kassinatuerin-1: a peptide with broad-spectrum antimicrobial activity isolated from the skin of the Hyperoliid frog, Kassinasenegalensis. Biochem Biophys Res Commun 2000; 268: 433-6.

Conlon JM, Abraham B, Galadari S, Knoop FC, Sonnevend A, Pál, T. Antimicrobial and cytolytic properties of the frog skin peptide, kassinatuerin-1 and its L- and D-lysine-substituted derivatives. Peptides 2005; 26: 2104-10.

Neonakis IK, Spandidos DA, Petinaki E. Confronting multidrug-resistant Acinetobacter baumannii: a review. Int J Antimicrob Agents 2011; 37: 102-9.

Karageorgopoulos DE, Falagas ME. Current control and treatment of multidrug-resistant Acinetobacter baumannii infections. Lancet Infect Dis 2008; 8: 751-62.

Sebeny PJ, Riddle MS, Petersen K. Acinetobacter baumannii skin and soft-tissue infection associated with war trauma. Clin Infect Dis 2008; 47: 444-9.

Giamarellou H, Poulakou G. Multidrug-resistant Gram-negative infections: what are the treatment options? Drugs 2009; 69: 1879-901.

Fishbain J, Peleg AY. Treatment of Acinetobacter infections. Clin Infect Dis 2010; 51: 79-84.

Conlon JM, Demandt A, Nielsen PF, Leprince J, Vaudry H, Woodhams DC. The alyteserins: two families of antimicrobial peptides from the skin secretions of the midwife toad Alytesobstetricans (Alytidae). Peptides 2009; 30: 1069-73.

Conlon JM, Ahmed E, Pal T, Sonnevend A. Potent and rapid bactericidal action of alyteserin-1c and its [E4K] analog against multidrug-resistant strains of Acinetobacter baumannii. Peptides 2010; 31: 1806- 10.

Bevier CR, Sonnevend A, Kolodziejek J, Nowotny N, Nielsen PF, Conlon JM. Purification and characterization of antimicrobial peptides from the skin secretions of the mink frog (Ranaseptentrionalis). Comp Biochem Physiol C 2004; 139: 31-8.

Conlon JM, Ahmed E, Condamine E. Antimicrobial properties of brevinin-2-related peptide and its analogs: Efficacy against multidrug-resistant Acinetobacter baumannii. Chem Biol Drug Des 2009; 74: 488-93.

Kawasaki H, Iwamuro S. Potential roles of histones in host defense as antimicrobial agents. Infect Disord Drug Targets 2008; 8: 195-205.

Kim HS, Yoon H, Minn I, Park CB, Lee WT, Zasloff, Kim SC. Pepsin-mediated processing of the cytoplasmic histone H2A to strong antimicrobial peptide buforin I. J Immunol 2000; 165: 3268-74.

Park CB, Kim HS, Kim SC. Mechanism of action of the antimicrobial peptide buforin II: buforin II kills microorganisms by penetrating the cell membrane and inhibiting cellular functions. Biochem Biophys Res Commun 1998; 244: 253-57.

Giacometti A, Cirioni O, Del Prete MS, Barchiesi F, Paggi AM, Petrelli E, et al. Comparative activities of polycationic peptides and clinically used antimicrobial agents against multidrug-resistant nosocomial isolates of Acinetobacter baumannii. J Antimicrob Chemother 2000; 46: 807-10.

Giacometti A, Cirioni O, Del Prete MS, Barchiesi F, Fortuna M, Drenaggi D, et al. In vitro activities of membrane-active peptides alone and in combination with clinically used antimicrobial agents against Stenotrophomonas maltophilia. Antimicrob Agents Chemother 2000; 44: 1716-19.

Miceli MH, Díaz JA, Lee SA. Emerging opportunistic yeast infections. Lancet Infect Dis 2011; 11: 142-51.

Arendrup MC. Epidemiology of invasive candidiasis. Curr Opin Crit Care 2010; 16: 445-52.

Richardson MD. Changing patterns and trends in systemic fungal infections. J Antimicrob Chemother 2005; 56 Suppl 1: i5-i11.

Pierce GE. Pseudomonas aeruginosa, Candida albicans, and device-related nosocomial infections: implications, trends, and potential approaches for control. J Ind Microbiol Biotechnol 2005; 32: 309-18.

Conlon JM, Sonnevend A, Patel M, Davidson C, Nielsen PF, Pál T. Isolation of peptides of the brevinin-1 family with potent candidacidal activity from the skin secretions of the frog Ranaboylii. J Pept Res 2003; 62: 207-13.

Pál T, Abraham B, Sonnevend A, Jumaa P, Conlon JM. Brevinin-1BYa: a naturally occurring peptide from frog skin with broad-spectrum antibacterial and antifungal properties. Int J Antimicrob Agents 2006; 27: 525-9.

Hossain MA, Guilhaudis L, Sonnevend A, Attoub S, van Lierop BJ, Robinson AJ, et al. Synthesis, conformational analysis and biological properties of a dicarba derivative of the antimicrobial peptide, brevinin-1BYa. Eur Biophys J 2011; in press.

Strateva T, Yordanov D. Pseudomonas aeruginosa - a phenomenon of bacterial resistance. J Med Microbiol 2009; 58: 1133-48.

Driscoll JA, Brody SL, Kollef MH. The epidemiology, pathogenesis and treatment of Pseudomonas aeruginosa infections. Drugs 2007; 67: 351-68.

Høiby N, Ciofu O, Bjarnsholt T. Pseudomonas aeruginosa biofilms in cystic fibrosis. Future Microbiol 2010; 5: 1663-74.

Mesaros N, Nordmann P, Plésiat P, Roussel-Delvallez M, Van Eldere J, Glupczynski Y, et al. Pseudomonas aeruginosa: resistance and therapeutic options at the turn of the new millennium. Clin Microbiol Infect 2007; 13: 560-78.

Conlon JM, Sonnevend A, Patel M, Al-Dhaheri K, Nielsen PF, Kolodziejek J, et al. A family of brevinin-2 peptides with potent activity against Pseudomonas aeruginosa from the skin of the Hokkaido frog, Ranapirica. Regul Pept 2004; 118: 135-41.

Simmaco M, Mignogna G, Barra D, Bossa F. Antimicrobial peptides from skin secretions of Ranaesculenta. Molecular cloning of cDNAs encoding esculentin and brevinins and isolation of new active peptides. J Biol Chem 1994; 269: 11956- 61.

Mangoni ML, Maisetta G, Di Luca M, Gaddi LM, Esin S, Florio W, et al. Comparative analysis of the bactericidal activities of amphibian peptide analogues against multidrug-resistant nosocomial bacterial strains. Antimicrob Agents Chemother 2008; 52: 85-91.

Gottler LM, Ramamoorthy A. Structure, membrane orientation, mechanism, and function of pexiganan - a highly potent antimicrobial peptide designed from magainin. Biochim BiophysActa 1788; 2009: 1680-6.

Ge Y, MacDonald DL, Holroyd KJ, Thornsberry C, Wexler H, Zasloff M. In vitro antibacterial properties of pexiganan, an analog of magainin. Antimicrob Agents Chemother 1999; 43: 782-8.

Ge Y, MacDonald D, Henry MM, Hait HI, Nelson KA, Lipsky BA, et al. In vitro susceptibility to pexiganan of bacteria isolated from infected diabetic foot ulcers. Diagn Microbiol Infect Dis 1999; 35: 45-53.

Lipsky BA, Holroyd KJ, Zasloff M. Topical versus systemic antimicrobial therapy for treating mildly infected diabetic foot ulcers: a randomized, controlled, double-blinded, multicenter trial of pexiganan cream. Clin Infect Dis 2008; 47: 1537-45.

Bhambri S, Del Rosso JQ, Bhambri A. Pathogenesis of acne vulgaris: recent advances. J Drugs Dermatol 2009; 8: 615-8.

Kurokawa I, Danby FW, Ju Q, Wang X, Xiang LF, Xia L, et al. New developments in our understanding of acne pathogenesis and treatment. Exp Dermatol 2009; 18: 821-32.

Patel M, Bowe WP, Heughebaert C, Shalita AR. The development of antimicrobial resistance due to the antibiotic treatment of acne vulgaris: a review. J Drugs Dermatol 2010; 9: 655-64.

Urbán E, Nagy E, Pál T, Sonnevend A, Conlon JM. Activities of four frog skin-derived antimicrobial peptides (temporin-1DRa, temporin-1Va and the melittin-related peptides AR-23 and RV-23) against anaerobic bacteria. Int J Antimicrob Agents 2007; 29: 317-21.

Marta Guarna M, Coulson R, Rubinchik E. Antiinflammatory activity of cationic peptides: application to the treatment of acne vulgaris. FEMS Microbiol Lett 2006; 257: 1-6.

Bowdish DM, Davidson DJ, Scott MG, Hancock RE. Immunomodulatory activities of small host defense peptides. Antimicrob Agents Chemother 2005; 49: 1727-32.

Gorr SU, Abdolhosseini M. Antimicrobial peptides and periodontal disease. J Clin Periodontol 2011; 38 (Suppl 11): 126-41.

Genco CA, Maloy WL, Kari UP, Motley M. Antimicrobial activity of magainin analogues against anaerobic oral pathogens. Int J Antimicrob Agents 2003; 21: 75-8.

Conlon JM, Al-Ghaferi N, Ahmed E, Meetani MA, Leprince J, Nielsen PF. Orthologs of magainin, PGLa, procaerulein-derived, and proxenopsinderived peptides from skin secretions of the octoploid frog Xenopusamieti (Pipidae). Peptides 2010; 31: 989-94.

Add comment 

Home  Editorial Board  Search  Current Issue  Archive Issues  Announcements  Aims & Scope  About the Journal  How to Submit  Contact Us
Find out how to become a part of the HMJ  |   CLICK HERE >>
© Copyright 2012 - 2013 HMJ - HAMDAN Medical Journal. All Rights Reserved         Website Developed By Cedar Solutions INDIA