1887

Abstract

The need for novel antibiotics in an era where antimicrobial resistance is on the rise, and the number of new approved antimicrobial drugs reaching the market is declining, is evident. The underused potential of post-translationally modified peptides for clinical use makes this class of peptides interesting candidates. In this study, we made use of the vast amounts of available genomic data and screened all publicly available prokaryotic genomes (~3000) to identify 394 novel head-to-tail cyclized antimicrobial peptides. To verify these in silico results, we isolated and characterized a novel antimicrobial peptide from Bacillus pumilus that we named pumilarin. Pumilarin was demonstrated to have a circular structure and showed antimicrobial activity against several indicator strains, including pathogens.

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2017-09-25
2020-09-23
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References

  1. Arnison PG, Bibb MJ, Bierbaum G, Bowers AA, Bugni TS et al. Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature. Nat Prod Rep 2013;30:108–160 [CrossRef][PubMed]
    [Google Scholar]
  2. Maqueda M, Sánchez-Hidalgo M, Fernández M, Montalbán-López M, Valdivia E et al. Genetic features of circular bacteriocins produced by gram-positive bacteria. FEMS Microbiol Rev 2008;32:2–22 [CrossRef][PubMed]
    [Google Scholar]
  3. Gabrielsen C, Brede DA, Nes IF, Diep DB. Circular bacteriocins: biosynthesis and mode of action. Appl Environ Microbiol 2014;80:6854–6862 [CrossRef][PubMed]
    [Google Scholar]
  4. Alvarez-Sieiro P, Montalbán-López M, Mu D, Kuipers OP. Bacteriocins of lactic acid bacteria: extending the family. Appl Microbiol Biotechnol 2016;100:2939–2951 [CrossRef][PubMed]
    [Google Scholar]
  5. Montalbán-López M, Sánchez-Hidalgo M, Cebrián R, Maqueda M. Discovering the bacterial circular proteins: bacteriocins, cyanobactins, and pilins. J Biol Chem 2012;287:27007–27013 [CrossRef][PubMed]
    [Google Scholar]
  6. Montalbán-López M, Martínez-Bueno M, Valdivia E, Maqueda M. Expression of linear permutated variants from circular enterocin AS-48. Biochimie 2011;93:549–555 [CrossRef][PubMed]
    [Google Scholar]
  7. Cascales L, Craik DJ. Naturally occurring circular proteins: distribution, biosynthesis and evolution. Org Biomol Chem 2010;8:5035–5047 [CrossRef][PubMed]
    [Google Scholar]
  8. Montalbán-López M, Spolaore B, Pinato O, Martínez-Bueno M, Valdivia E et al. Characterization of linear forms of the circular enterocin AS-48 obtained by limited proteolysis. FEBS Lett 2008;582:3237–3242 [CrossRef][PubMed]
    [Google Scholar]
  9. Cotter PD, Ross RP, Hill C. Bacteriocins – a viable alternative to antibiotics?. Nat Rev Microbiol 2013;11:95–105 [CrossRef][PubMed]
    [Google Scholar]
  10. Montalbán-López M, Sánchez-Hidalgo M, Valdivia E, Martínez-Bueno M, Maqueda M. Are bacteriocins underexploited? Novel applications for old antimicrobials. Curr Pharm Biotechnol 2011;12:1205–1220 [CrossRef][PubMed]
    [Google Scholar]
  11. Cotter PD, Hill C, Ross RP. Bacteriocins: developing innate immunity for food. Nat Rev Microbiol 2005;3:777–788 [CrossRef][PubMed]
    [Google Scholar]
  12. Maqueda Abreu M, Martínez Bueno M, Valdivia Martínez E, Ananou Jaled S, Cebrián Castillo R. Composition for treating bacterial infections of the skin and mucous membranes. International Patent 2014;2014006253
    [Google Scholar]
  13. Rink R, Arkema-Meter A, Baudoin I, Post E, Kuipers A et al. To protect peptide pharmaceuticals against peptidases. J Pharmacol Toxicol Methods 2010;61:210–218 [CrossRef][PubMed]
    [Google Scholar]
  14. Moll GN, Kuipers A, Rink R. Microbial engineering of dehydro-amino acids and lanthionines in non-lantibiotic peptides. Antonie van Leeuwenhoek 2010;97:319–333 [CrossRef][PubMed]
    [Google Scholar]
  15. Hemu X, Qiu Y, Nguyen GK, Tam JP. Total synthesis of circular bacteriocins by butelase 1. J Am Chem Soc 2016;138:6968–6971 [CrossRef][PubMed]
    [Google Scholar]
  16. Stanger K, Maurer T, Kaluarachchi H, Coons M, Franke Y et al. Backbone cyclization of a recombinant cystine-knot peptide by engineered sortase A. FEBS Lett 2014;588:4487–4496 [CrossRef][PubMed]
    [Google Scholar]
  17. Acedo JZ, van Belkum MJ, Lohans CT, Towle KM, Miskolzie M et al. Nuclear magnetic resonance solution structures of lacticin Q and aureocin A53 reveal a structural motif conserved among leaderless bacteriocins with broad-spectrum activity. Biochemistry 2016;55:733–742 [CrossRef][PubMed]
    [Google Scholar]
  18. González C, Langdon GM, Bruix M, Gálvez A, Valdivia E et al. Bacteriocin AS-48, a microbial cyclic polypeptide structurally and functionally related to mammalian NK-lysin. Proc Natl Acad Sci USA 2000;97:11221–11226 [CrossRef][PubMed]
    [Google Scholar]
  19. van Belkum MJ, Martin-Visscher LA, Vederas JC. Structure and genetics of circular bacteriocins. Trends Microbiol 2011;19:411–418 [CrossRef][PubMed]
    [Google Scholar]
  20. Gong X, Martin-Visscher LA, Nahirney D, Vederas JC, Duszyk M. The circular bacteriocin, carnocyclin A, forms anion-selective channels in lipid bilayers. Biochim Biophys Acta 2009;1788:1797–1803 [CrossRef][PubMed]
    [Google Scholar]
  21. Martin-Visscher LA, Gong X, Duszyk M, Vederas JC. The three-dimensional structure of carnocyclin A reveals that many circular bacteriocins share a common structural motif. J Biol Chem 2009;284:28674–28681 [CrossRef][PubMed]
    [Google Scholar]
  22. Cebrián R, Martínez-Bueno M, Valdivia E, Albert A, Maqueda M et al. The bacteriocin AS-48 requires dimer dissociation followed by hydrophobic interactions with the membrane for antibacterial activity. J Struct Biol 2015;190:162–172 [CrossRef][PubMed]
    [Google Scholar]
  23. Cruz VL, Ramos J, Melo MN, Martinez-Salazar J. Bacteriocin AS-48 binding to model membranes and pore formation as revealed by coarse-grained simulations. Biochim Biophys Acta 2013;1828:2524–2531 [CrossRef][PubMed]
    [Google Scholar]
  24. Gabrielsen C, Brede DA, Hernández PE, Nes IF, Diep DB. The maltose ABC transporter in Lactococcus lactis facilitates high-level sensitivity to the circular bacteriocin garvicin ML. Antimicrob Agents Chemother 2012;56:2908–2915 [CrossRef][PubMed]
    [Google Scholar]
  25. Maqueda M, Gálvez A, Bueno MM, Sanchez-Barrena MJ, González C et al. Peptide AS-48: prototype of a new class of cyclic bacteriocins. Curr Protein Pept Sci 2004;5:399–416 [CrossRef][PubMed]
    [Google Scholar]
  26. Sánchez-Hidalgo M, Montalbán-López M, Cebrián R, Valdivia E, Martínez-Bueno M et al. AS-48 bacteriocin: close to perfection. Cell Mol Life Sci 2011;68:2845–2857 [CrossRef][PubMed]
    [Google Scholar]
  27. Martínez-Bueno M, Valdivia E, Gálvez A, Coyette J, Maqueda M. Analysis of the gene cluster involved in production and immunity of the peptide antibiotic AS-48 in Enterococcus faecalis. Mol Microbiol 1998;27:347–358 [CrossRef][PubMed]
    [Google Scholar]
  28. Tomita H, Fujimoto S, Tanimoto K, Ike Y. Cloning and genetic and sequence analyses of the bacteriocin 21 determinant encoded on the Enterococcus faecalis pheromone-responsive conjugative plasmid pPD1. J Bacteriol 1997;179:7843–7855 [CrossRef][PubMed]
    [Google Scholar]
  29. Joosten HM, Nunez M, Devreese B, van Beeumen J, Marugg JD. Purification and characterization of enterocin 4, a bacteriocin produced by Enterococcus faecalis INIA 4. Appl Environ Microbiol 1996;62:4220–4223[PubMed]
    [Google Scholar]
  30. Maisnier-Patin S, Forni E, Richard J. Purification, partial characterisation and mode of action of enterococcin EFS2, an antilisterial bacteriocin produced by a strain of Enterococcus faecalis isolated from a cheese. Int J Food Microbiol 1996;30:255–270 [CrossRef][PubMed]
    [Google Scholar]
  31. Cebrián R, Baños A, Valdivia E, Pérez-Pulido R, Martínez-Bueno M et al. Characterization of functional, safety, and probiotic properties of Enterococcus faecalis UGRA10, a new AS-48-producer strain. Food Microbiol 2012;30:59–67 [CrossRef][PubMed]
    [Google Scholar]
  32. Huang E, Zhang L, Chung YK, Zheng Z, Yousef AE. Characterization and application of enterocin RM6, a bacteriocin from Enterococcus faecalis. Biomed Res Int 2013;2013:206917 [CrossRef][PubMed]
    [Google Scholar]
  33. Abriouel H, Lucas R, Ben Omar N, Valdivia E, Maqueda M et al. Enterocin AS-48RJ: a variant of enterocin AS-48 chromosomally encoded by Enterococcus faecium RJ16 isolated from food. Syst Appl Microbiol 2005;28:383–397 [CrossRef][PubMed]
    [Google Scholar]
  34. Martínez-Bueno M, Gálvez A, Valdivia E, Maqueda M. A transferable plasmid associated with AS-48 production in Enterococcus faecalis. J Bacteriol 1990;172:2817–2818 [CrossRef][PubMed]
    [Google Scholar]
  35. Diaz M, Valdivia E, Martínez-Bueno M, Fernández M, Soler-González AS et al. Characterization of a new operon, as-48EFGH, from the as-48 gene cluster involved in immunity to enterocin AS-48. Appl Environ Microbiol 2003;69:1229–1236 [CrossRef][PubMed]
    [Google Scholar]
  36. Mu F, Masuda Y, Zendo T, Ono H, Kitagawa H et al. Biological function of a DUF95 superfamily protein involved in the biosynthesis of a circular bacteriocin, leucocyclicin Q. J Biosci Bioeng 2014;117:158–164 [CrossRef][PubMed]
    [Google Scholar]
  37. Blin K, Medema MH, Kazempour D, Fischbach MA, Breitling R et al. antiSMASH 2.0-a versatile platform for genome mining of secondary metabolite producers. Nucleic Acids Res 2013;41:W204–W212 [CrossRef][PubMed]
    [Google Scholar]
  38. van Heel AJ, de Jong A, Montalbán-López M, Kok J, Kuipers OP. BAGEL3: automated identification of genes encoding bacteriocins and (non-)bactericidal posttranslationally modified peptides. Nucleic Acids Res 2013;41:W448–W453 [CrossRef][PubMed]
    [Google Scholar]
  39. Kersten RD, Yang YL, Xu Y, Cimermancic P, Nam SJ et al. A mass spectrometry-guided genome mining approach for natural product peptidogenomics. Nat Chem Biol 2011;7:794–802 [CrossRef][PubMed]
    [Google Scholar]
  40. Montalbán-López M, Van Heel AJ, Kuipers OP. Employing the promiscuity of lantibiotic biosynthetic machineries to produce novel antimicrobials. FEMS Microbiol Rev 2017;41:5–18 [CrossRef][PubMed]
    [Google Scholar]
  41. Begley M, Cotter PD, Hill C, Ross RP. Identification of a novel two-peptide lantibiotic, lichenicidin, following rational genome mining for LanM proteins. Appl Environ Microbiol 2009;75:5451–5460 [CrossRef][PubMed]
    [Google Scholar]
  42. Li B, Sher D, Kelly L, Shi Y, Huang K et al. Catalytic promiscuity in the biosynthesis of cyclic peptide secondary metabolites in planktonic marine cyanobacteria. Proc Natl Acad Sci USA 2010;107:10430–10435 [CrossRef][PubMed]
    [Google Scholar]
  43. De Jong A, Van Heel AJ, Montalban-Lopez M, Krawczyk AO, Berendsen EM et al. Draft genome sequences of five spore-forming food isolates of Bacillus pumilus. Genome Announc 2015;3:e01539-14 [CrossRef][PubMed]
    [Google Scholar]
  44. Gálvez A, Maqueda M, Valdivia E, Quesada A, Montoya E. Characterization and partial purification of a broad spectrum antibiotic AS-48 produced by Streptococcus faecalis. Can J Microbiol 1986;32:765–771 [CrossRef][PubMed]
    [Google Scholar]
  45. Abriouel H, Valdivia E, Martínez-Bueno M, Maqueda M, Gálvez A. A simple method for semi-preparative-scale production and recovery of enterocin AS-48 derived from Enterococcus faecalis subsp. liquefaciens A-48-32. J Microbiol Methods 2003;55:599–605 [CrossRef][PubMed]
    [Google Scholar]
  46. van Heel AJ, Mu D, Montalbán-López M, Hendriks D, Kuipers OP. Designing and producing modified, new-to-nature peptides with antimicrobial activity by use of a combination of various lantibiotic modification enzymes. ACS Synth Biol 2013;2:397–404 [CrossRef][PubMed]
    [Google Scholar]
  47. Rink R, Kuipers A, de Boef E, Leenhouts KJ, Driessen AJ et al. Lantibiotic structures as guidelines for the design of peptides that can be modified by lantibiotic enzymes. Biochemistry 2005;44:8873–8882 [CrossRef][PubMed]
    [Google Scholar]
  48. Jones DT. Protein secondary structure prediction based on position-specific scoring matrices. J Mol Biol 1999;292:195–202 [CrossRef][PubMed]
    [Google Scholar]
  49. Buchan DW, Minneci F, Nugent TC, Bryson K, Jones DT. Scalable web services for the PSIPRED protein analysis workbench. Nucleic Acids Res 2013;41:W349–W357 [CrossRef][PubMed]
    [Google Scholar]
  50. Gabrielsen C, Brede DA, Salehian Z, Nes IF, Diep DB. Functional genetic analysis of the GarML gene cluster in Lactococcus garvieae DCC43 gives new insights into circular bacteriocin biosynthesis. J Bacteriol 2014;196:911–919 [CrossRef][PubMed]
    [Google Scholar]
  51. Himeno K, Rosengren KJ, Inoue T, Perez RH, Colgrave ML et al. Identification, characterization, and three-dimensional structure of the novel circular bacteriocin, enterocin NKR-5-3B, from Enterococcus faecium. Biochemistry 2015;54:4863–4876 [CrossRef][PubMed]
    [Google Scholar]
  52. Cebrián R, Maqueda M, Neira JL, Valdivia E, Martínez-Bueno M et al. Insights into the functionality of the putative residues involved in enterocin AS-48 maturation. Appl Environ Microbiol 2010;76:7268–7276 [CrossRef][PubMed]
    [Google Scholar]
  53. Oman TJ, van der Donk WA. Follow the leader: the use of leader peptides to guide natural product biosynthesis. Nat Chem Biol 2010;6:9–18 [CrossRef][PubMed]
    [Google Scholar]
  54. Plat A, Kuipers A, Rink R, Moll GN. Mechanistic aspects of lanthipeptide leaders. Curr Protein Pept Sci 2013;14:85–96 [CrossRef][PubMed]
    [Google Scholar]
  55. Cebrián R, Rodríguez-Ruano S, Martínez-Bueno M, Valdivia E, Maqueda M et al. Analysis of the promoters involved in enterocin AS-48 expression. PLoS One 2014;9:e90603 [CrossRef][PubMed]
    [Google Scholar]
  56. Heinzmann S, Entian KD, Stein T. Engineering Bacillus subtilis ATCC 6633 for improved production of the lantibiotic subtilin. Appl Microbiol Biotechnol 2006;69:532–536 [CrossRef][PubMed]
    [Google Scholar]
  57. Sánchez-Barrena MJ, Martínez-Ripoll M, Gálvez A, Valdivia E, Maqueda M et al. Structure of bacteriocin AS-48: from soluble state to membrane bound state. J Mol Biol 2003;334:541–549 [CrossRef][PubMed]
    [Google Scholar]
  58. Sánchez-Hidalgo M, Martínez-Bueno M, Fernández-Escamilla AM, Valdivia E, Serrano L et al. Effect of replacing glutamic residues upon the biological activity and stability of the circular enterocin AS-48. J Antimicrob Chemother 2008;61:1256–1265 [CrossRef][PubMed]
    [Google Scholar]
  59. Masuda Y, Ono H, Kitagawa H, Ito H, Mu F et al. Identification and characterization of leucocyclicin Q, a novel cyclic bacteriocin produced by Leuconostoc mesenteroides TK41401. Appl Environ Microbiol 2011;77:8164–8170 [CrossRef][PubMed]
    [Google Scholar]
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