Advertisement

Identification of an Ultra-Short Peptide with Potent Pseudomonas aeruginosa Activity for Development as a Topical Antibacterial Agent

  • Shu Wei Teo
  • Yaqing Elena Yong
  • Siew Mei Samantha Ng
  • Fui Mee Ng
  • Jeanette Woon Pei Teo
  • Roland Jureen
  • Jeffrey Hill
  • C. S. Brian ChiaEmail author
Short Communication
  • 127 Downloads

Abstract

Pseudomonas aeruginosa is a Gram-negative pathogen responsible for a wide spectrum of infections including skin-related infections such as ecthyma gangrenosum, folliculitis, surgical site and burn wound infections. The global emergence of drug-resistant strains has become a clinical concern and new antibacterial agents are urgently needed. Antimicrobial peptides, with their membrane-disrupting mode of action, are deemed potential candidates. Herein, we screened 62 published short peptides, up to 11 residues in length, with reported antibacterial properties, against a multidrug-resistant strain of P. aeruginosa. Of the 3 most potent peptides, the shortest one was selected for further studies involving a panel of clinical P. aeruginosa strains, a bactericidal/static determination assay and a time-kill assay to gauge its potential for further development as a topical antibacterial drug candidate.

Keywords

Antimicrobial peptides Broad-spectrum antibiotic Pseudomonas aeruginosa 

Notes

Acknowledgements

The authors thank the Agency for Science, Technology and Research Biomedical Research Council for funding.

Compliance with Ethical Standards

Conflict of interest

The authors of this paper declare no conflicts of interest.

References

  1. Abbassi F, Lequin O, Piesse C, Goasdoué N, Foulon T, Nicolas P, Ladram A (2010) Temporin-SHf, a new type of phe-rich and hydrophobic ultrashort antimicrobial peptide. J Biol Chem 285:16880–16892.  https://doi.org/10.1074/jbc.M109.097204 CrossRefGoogle Scholar
  2. Ahmad A, Ahmad E, Rabbani G, Haque S, Arshad M, Khan RH (2012) Identification and design of antimicrobial peptides for therapeutic applications. Curr Protein Pept Sci 13:211–223.  https://doi.org/10.2174/138920312800785076 CrossRefGoogle Scholar
  3. Asoodeh A, Zardini HZ, Chamani J (2012) Identification and characterization of two novel antimicrobial peptides, temporin-Ra and temporin-Rb, from skin secretions of the marsh frog Rana ridibunda. J Pept Sci 18:10–16.  https://doi.org/10.1002/psc.1409 CrossRefGoogle Scholar
  4. Bai Y, Liu S, Jiang P, Zhou L, Li J, Tang C, Verma C, Mu Y, Beuerman RW, Pervushin K (2009) Structure-dependent charge density as a determinant of antimicrobial activity of peptide analogues of defensin. Biochemistry 48:7229–7239.  https://doi.org/10.1021/bi900670d CrossRefGoogle Scholar
  5. Brogden NK, Brogden KA (2011) Will new generations of modified antimicrobial peptides improve their potential as pharmaceuticals? Int J Antimicrob Agents 38:217–225.  https://doi.org/10.1016/j.ijantimicag.2011.05.004 Google Scholar
  6. Catiau L, Traisnel J, Chihib NE, Le Flem G, Blanpain A, Melnyk O, Guillochon D, Nedjar-Arroume N (2011a) RYH: a minimal peptidic sequence obtained from beta-chain hemoglobin exhibiting an antimicrobial activity. Peptides 32:1463–1468.  https://doi.org/10.1016/j.peptides.2011.05.021 CrossRefGoogle Scholar
  7. Catiau L, Traisnel J, Delval-Dubois V, Chihib NE, Guillochon D, Nedjar-Arroume N (2011b) Minimal antimicrobial peptidic sequence from hemoglobin alpha-chain: KYR. Peptides 32:633–638.  https://doi.org/10.1016/j.peptides.2010.12.016 CrossRefGoogle Scholar
  8. Chan DI, Prenner EJ, Vogel HJ (2006) Tryptophan- and arginine-rich antimicrobial peptides: structures and mechanisms of action. Biochim Biophys Acta 1758:1184–1202.  https://doi.org/10.1016/j.bbamem.2006.04.006 CrossRefGoogle Scholar
  9. Chen C, Pan F, Zhang S, Hu J, Cao M, Wang J, Xu H, Zhao X, Lu JR (2010) Antibacterial activities of short designer peptides: a link between propensity for nanostructuring and capacity for membrane destabilization. Biomacromol 11:402–411.  https://doi.org/10.1021/bm901130u CrossRefGoogle Scholar
  10. Cherkasov A, Hilpert K, Jenssen H, Fjell CD, Waldbrook M, Mullaly SC, Volkmer R, Hancock REW (2009) Use of artificial intelligence in the design of small peptide antibiotics effective against a broad spectrum of highly antibiotic-resistant superbugs. ACS Chem Biol 4:65–74.  https://doi.org/10.1021/cb800240j CrossRefGoogle Scholar
  11. Clinical and Laboratory Standards Institute (2012) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, approved standard, 9th edn. Document M07-A9; CLSI: Wayne, PA, USA, 32, No. 2Google Scholar
  12. de la Fuente-Núñez C, Korolik V, Bains M, Nguyen U, Breidenstein EB, Horsman S, Lewenza S, Burrows L, Hancock REW (2012) Inhibition of bacterial biofilm formation and swarming motility by a small synthetic cationic peptide. Antimicrob Agents Chemother 56:2696–2704.  https://doi.org/10.1128/AAC.00064-12 CrossRefGoogle Scholar
  13. Dryden MS (2010) Complicated skin and soft tissue infection. J Antimicrob Chemother 65:S35-S44.  https://doi.org/10.1093/jac/dkq302 CrossRefGoogle Scholar
  14. Fjell CD, Jenssen H, Hilpert K, Cheung WA, Panté N, Hancock REW, Cherkasov A (2009) Identification of novel antibacterial peptides by chemoinformatics and machine learning. J Med Chem 52:2006–2015.  https://doi.org/10.1021/jm8015365 CrossRefGoogle Scholar
  15. Fjell CD, Jenssen H, Cheung WA, Hancock REW, Cherkasov A (2011) Optimization of antibacterial peptides by genetic algorithms and cheminformatics. Chem Biol Drug Des 77:48–56.  https://doi.org/10.1111/j.1747-0285.2010.01044.x CrossRefGoogle Scholar
  16. Flamm RK, Rhomberg PR, Simpson KM, Farrell DJ, Sader HS, Jones RN (2015) In vitro spectrum of pexiganan activity when tested against pathogens from diabetic foot infections and with selected resistance mechanisms. Antimicrob Agents Chemother 59:1751–1754.  https://doi.org/10.1128/AAC.04773-14 CrossRefGoogle Scholar
  17. French GL (2006) Bactericidal agents in the treatment of MRSA infections: the potential role of daptomycin. J Antimicrob Chemother 58:1107–1117.  https://doi.org/10.1093/jac/dkl393 CrossRefGoogle Scholar
  18. Frieden T (2013) Antibiotic resistance threats in the United States, 2013. Executive Summary. Centers for Disease Control and Prevention, Atlanta: http://www.cdc.gov/drugresistance/threat-report-2013/. Accessed 1 August 2017
  19. Gopal R, Seo CH, Song PI, Park Y (2013) Effect of repetitive lysine-tryptophan motifs on the bactericidal activity of antimicrobial peptides. Amino Acids 44:645–660.  https://doi.org/10.1007/s00726-012-1388-6 CrossRefGoogle Scholar
  20. Guzmán F, Marshall S, Ojeda C, Albericio F, Carvajal-Rondanelli P (2013) Inhibitory effect of short cationic homopeptides against gram-positive bacteria. J Pept Sci 19:792–800.  https://doi.org/10.1002/psc.2578 CrossRefGoogle Scholar
  21. Hancock REW, Sahl H (2006) Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 24:1551–1557.  https://doi.org/10.1038/nbt1267 CrossRefGoogle Scholar
  22. Haney EF, Mansour SC, Hancock RE (2017) Antimicrobial peptides: an introduction. Methods Mol Biol 1548:3–22.  https://doi.org/10.1007/978-1-4939-6737-7_1 CrossRefGoogle Scholar
  23. Hilpert K, Volkmer-Engert R, Walter T, Hancock REW (2005) High-throughput generation of small antibacterial peptides with improved activity. Nat Biotechnol 23:1008–1012.  https://doi.org/10.1038/nbt1113 CrossRefGoogle Scholar
  24. Hilpert K, Elliott M, Jenssen H, Kindrachuk J, Fjell CD, Körner J, Winkler DF, Weaver LL, Henklein P, Ulrich AS, Chiang SH, Farmer SW, Pante N, Volkmer R, Hancock REW (2009) Screening and characterization of surface-tethered cationic peptides for antimicrobial activity. Chem Biol 16:58–69.  https://doi.org/10.1016/j.chembiol.2008.11.006 CrossRefGoogle Scholar
  25. Hou X, Du Q, Li R, Zhou M, Wang H, Wang L, Guo C, Shaw C (2015) Feleucin-BO1: a novel antimicrobial non-apeptide amide from the skin secretion of the toad, Bombina orientalis, and design of a potent broad-spectrum synthetic analogue, feleucin-K3. Chem Biol Drug Des 85:259–267.  https://doi.org/10.1111/cbdd.12396 CrossRefGoogle Scholar
  26. Iannucci NB, Curto LM, Albericio F, Cascone O, Delfino JM (2014) Structural glance into a novel anti-staphylococcal peptide. Biopolymers 102:49–57.  https://doi.org/10.1002/bip.22394 CrossRefGoogle Scholar
  27. Juba M, Porter D, Dean S, Gillmor S, Bishop B (2013) Characterization and performance of short cationic antimicrobial peptide isomers. Biopolymers 100:387–401.  https://doi.org/10.1002/bip.22244 CrossRefGoogle Scholar
  28. Kang SJ, Won HS, Choi WS, Lee BJ (2009) De novo generation of antimicrobial LK peptides with a single tryptophan at the critical amphipathic interface. J Pept Sci 15:583–588.  https://doi.org/10.1002/psc.1149 CrossRefGoogle Scholar
  29. Kerr KG, Snelling AM (2009) Pseudomonas aeruginosa: a formidable and ever-present adversary. J Hosp Infect 73:338–344.  https://doi.org/10.1016/j.jhin.2009.04.020 CrossRefGoogle Scholar
  30. Konno K, Rangel M, Oliveira JS, Dos Santos Cabrera MP, Fontana R, Hirata IY, Hide I, Nakata Y, Mori K, Kawano M, Fuchino H, Sekita S, Neto JR (2007) Decoralin, a novel linear cationic alpha-helical peptide from the venom of the solitary eumenine wasp Oreumenes decoratus. Peptides 28:2320–2327.  https://doi.org/10.1016/j.peptides.2007.09.017 CrossRefGoogle Scholar
  31. Kukowska M, Kukowska-Kaszuba M, Dzierzbicka K (2015) In vitro studies of antimicrobial activity of Gly-His-Lys conjugates as potential and promising candidates for therapeutics in skin and tissue infections. Bioorg Med Chem Lett 25:542–546.  https://doi.org/10.1016/j.bmcl.2014.12.029 CrossRefGoogle Scholar
  32. Lee SH, Kim SJ, Lee YS, Song MD, Kim IH, Won HS (2011) De novo generation of short antimicrobial peptides with simple amino acid composition. Regul Pept 166:36–41.  https://doi.org/10.1016/j.regpep.2010.08.010 CrossRefGoogle Scholar
  33. Li X, Li P, Saravanan R, Basu A, Mishra B, Lim SH, Su X, Tambyah P, Leong SSJ (2014) Antimicrobial functionalization of silicone surfaces with engineered short peptides having broad spectrum antimicrobial and salt-resistant properties. Acta Biomater 10:258–266.  https://doi.org/10.1016/j.actbio.2013.09.009 CrossRefGoogle Scholar
  34. Lim K, Chua RR, Saravanan R, Basu A, Mishra B, Tambyah PA, Ho B, Leong SSJ (2013) Immobilization studies of an engineered arginine-tryptophan-rich peptide on a silicone surface with antimicrobial and antibiofilm activity. ACS Appl Mater Interfaces 5:6412–6422.  https://doi.org/10.1021/am401629p CrossRefGoogle Scholar
  35. Liu Z, Brady A, Young A, Rasimick B, Chen K, Zhou C, Kallenbach NR (2007) Length effects in antimicrobial peptides of the (RW)n series. Antimicrob Agents Chemother 51:597–603.  https://doi.org/10.1128/AAC.00828-06 CrossRefGoogle Scholar
  36. Lung FD, Wang KS, Liao ZJ, Hsu SK, Song FY, Liou CC, Wu YS (2012) Discovery of potent antimicrobial peptide analogs of Ixosin-B. Bioorg Med Chem Lett 22:4185–4188.  https://doi.org/10.1016/j.bmcl.2012.04.018 CrossRefGoogle Scholar
  37. Mohamed MF, Hamed MI, Panitch A, Seleem MN (2014) Targeting methicillin-resistant Staphylococcus aureus with short salt-resistant synthetic peptides. Antimicrob Agents Chemother 58:4113–4122.  https://doi.org/10.1128/AAC.02578-14 CrossRefGoogle Scholar
  38. Munk JK, Uggerhøj LE, Poulsen TJ, Frimodt-Møller N, Wimmer R, Nyberg NT, Hansen PR (2013) Synthetic analogs of anoplin show improved antimicrobial activities. J Pept Sci 19:669–675.  https://doi.org/10.1002/psc.2548 CrossRefGoogle Scholar
  39. Murugan RN, Jacob B, Kim EH, Ahn M, Sohn H, Seo JH, Cheong C, Hyun JK, Lee KS, Shin SY, Bang JK (2013) Non hemolytic short peptidomimetics as a new class of potent and broad-spectrum antimicrobial agents. Bioorg Med Chem Lett 23:4633–4636.  https://doi.org/10.1016/j.bmcl.2013.06.016 CrossRefGoogle Scholar
  40. Naidoo VB, Rautenbach M (2013) Self-assembling organo-peptide bolaphiles with KLK tripeptide head groups display selective antibacterial activity. J Pept Sci 19:784–791.  https://doi.org/10.1002/psc.2576 CrossRefGoogle Scholar
  41. Ong ZY, Gao SJ, Yang YY (2013) Short synthetic β-sheet forming peptide amphiphiles as broad spectrum antimicrobials with antibiofilm and endotoxin neutralizing capabilities. Adv Funct Mater 23:3682–3692.  https://doi.org/10.1002/adfm.201202850 CrossRefGoogle Scholar
  42. Park KH, Park Y, Park IS, Hahm KS, Shin SY (2008) Bacterial selectivity and plausible mode of antibacterial action of designed pro-rich short model antimicrobial peptides. J Pept Sci 14:876–882.  https://doi.org/10.1002/psc.1019 CrossRefGoogle Scholar
  43. Park KH, Nan YH, Park Y, Kim JI, Park IS, Hahm KS, Shin SY (2009) Cell specificity, anti-inflammatory activity, and plausible bactericidal mechanism of designed Trp-rich model antimicrobial peptides. Biochim Biophys Acta 1788:1193–1203.  https://doi.org/10.1016/j.bbamem.2009.02.020 CrossRefGoogle Scholar
  44. Pasupuleti M, Schmidtchen A, Chalupka A, Ringstad L, Malmsten M (2009) End-tagging of ultra-short antimicrobial peptides by W/F stretches to facilitate bacterial killing. PLoS ONE 4:e5285.  https://doi.org/10.1371/journal.pone.0005285 CrossRefGoogle Scholar
  45. Qi X, Zhou C, Li P, Xu W, Cao Y, Ling H, Chen WN, Li CM, Xu R, Lamrani M, Mu Y, Leong SSJ, Chang MW, Chan-Park MB (2010) Novel short antibacterial and antifungal peptides with low cytotoxicity: efficacy and action mechanisms. Biochem Biophys Res Commun 398:594–600.  https://doi.org/10.1016/j.bbrc.2010.06.131 CrossRefGoogle Scholar
  46. Ramón-García S, Mikut R, Ng C, Ruden S, Volkmer R, Reischl M, Hilpert K, Thompson CJ (2013) Targeting Mycobacterium tuberculosis and other microbial pathogens using improved synthetic antibacterial peptides. Antimicrob Agents Chemother 57:2295–2303.  https://doi.org/10.1128/AAC.00175-13 CrossRefGoogle Scholar
  47. Rathinakumar R, Walkenhorst WF, Wimley WC (2009) Broad-spectrum antimicrobial peptides by rational combinatorial design and high-throughput screening: the importance of interfacial activity. J Am Chem Soc 131:7609–7617.  https://doi.org/10.1021/ja8093247 CrossRefGoogle Scholar
  48. Romanelli A, Moggio L, Montella RC, Campiglia P, Iannaccone M, Capuano F, Pedone C, Capparelli R (2011) Peptides from royal jelly: studies on the antimicrobial activity of jelleins, jelleins analogs and synergy with temporins. J Pept Sci 17:348–352.  https://doi.org/10.1002/psc.1316 CrossRefGoogle Scholar
  49. Shin S, Kim JK, Lee JY, Jung KW, Hwang JS, Lee J, Lee DG, Kim I, Shin SY, Kim Y (2009) Design of potent 9-mer antimicrobial peptide analogs of protaetiamycine and investigation of mechanism of antimicrobial action. J Pept Sci 15:559–568.  https://doi.org/10.1002/psc.1156 CrossRefGoogle Scholar
  50. Singh K, Kumar S, Shekhar S, Dhawan B, Dey S (2014) Synthesis and biological evaluation of novel peptide BF2 as an antibacterial agent against clinical isolates of vancomycin-resistant enterococci. J Med Chem 57:8880–8885.  https://doi.org/10.1021/jm500960s CrossRefGoogle Scholar
  51. Spindler EC, Hale JD, Giddings TH Jr, Hancock REW, Gill RT (2011) Deciphering the mode of action of the synthetic antimicrobial peptide Bac8c. Antimicrob Agents Chemother 55:1706–1716.  https://doi.org/10.1128/AAC.01053-10 CrossRefGoogle Scholar
  52. Sundriyal S, Sharma RK, Jain R, Bharatam PV (2008) Minimum requirements of hydrophobic and hydrophilic features in cationic peptide antibiotics (CPAs). J Mol Model 14:265–278.  https://doi.org/10.1007/s00894-008-0268-1 CrossRefGoogle Scholar
  53. Torcato IM, Huang YH, Franquelim HG, Gaspar D, Craik DJ, Castanho MARB, Henriques ST (2013) Design and characterization of novel antimicrobial peptides, R-BP100 and RW-BP100, with activity against Gram-negative and Gram-positive bacteria. Biochim Biophys Acta 1828:944–955.  https://doi.org/10.1016/j.bbamem.2012.12.002 CrossRefGoogle Scholar
  54. Wagner S, Sommer R, Hinsberger S, Lu C, Hartmann RW, Empting M, Titz A (2016) Novel strategies for the treatment of Pseudomonas aeruginosa infections. J Med Chem 59:5929–5969.  https://doi.org/10.1021/acs.jmedchem.5b01698 CrossRefGoogle Scholar
  55. Wang Y, Chen J, Zheng X, Yang X, Ma P, Cai Y, Zhang B, Chen Y (2014) Design of novel analogues of short antimicrobial peptide anoplin with improved antimicrobial activity. J Pept Sci 20:945–951.  https://doi.org/10.1002/psc.2705 CrossRefGoogle Scholar
  56. Wang G, Li X, Wang Z (2016) APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res 44:D1087–D1093.  https://doi.org/10.1093/nar/gkv1278 CrossRefGoogle Scholar
  57. Wei SY, Wu JM, Kuo YY, Chen HL, Yip BS, Tzeng SR, Cheng JW (2006) Solution structure of a novel tryptophan-rich peptide with bidirectional antimicrobial activity. J Bacteriol 188:328–334.  https://doi.org/10.1128/JB.188.1.328-334.2006 CrossRefGoogle Scholar
  58. Yang X, Wang Y, Lee WH, Zhang Y (2013) Antimicrobial peptides from the venom gland of the social wasp Vespa tropica. Toxicon 74:151–157.  https://doi.org/10.1016/j.toxicon.2013.08.056 CrossRefGoogle Scholar
  59. Zasloff M (2002) Antimicrobial peptides of multicellular organisms. Nature 415:389–395.  https://doi.org/10.1038/415389a CrossRefGoogle Scholar
  60. Zhou L, Liu SP, Chen LY, Li J, Ong LB, Guo L, Wohland T, Tang CC, Lakshminarayanan R, Mavinahalli J, Verma C, Beuerman RW (2011) The structural parameters for antimicrobial activity, human epithelial cell cytotoxicity and killing mechanism of synthetic monomer and dimer analogues derived from hBD3 C-terminal region. Amino Acids 40:123–133.  https://doi.org/10.1007/s00726-010-0565-8 CrossRefGoogle Scholar
  61. Zorko M, Japelj B, Hafner-Bratkovic I, Jerala R (2009) Expression, purification and structural studies of a short antimicrobial peptide. Biochim Biophys Acta 1788:314–323.  https://doi.org/10.1016/j.bbamem.2008.10.015 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR)SingaporeSingapore
  2. 2.Department of Laboratory MedicineNational University HospitalSingaporeSingapore

Personalised recommendations