Skip to main content
SpringerLink
Log in

Alpha-beta chimeric polypeptide molecular brushes display potent activity against superbugs-methicillin resistant Staphylococcus aureus

具有高效抗MRSA活性的Alpha-Beta杂化多肽聚合物分子刷

  • Letters
  • Published:
Science China Materials Aims and scope Submit manuscript

摘要

近年来, 以耐甲氧西林金黄色葡萄球菌(MRSA)为代表的“超级细菌”不断被发现和扩散, 已经严重威胁人类健康, 因此, 研制新型、 高效的抗菌剂迫在眉睫. 以宿主防御肽及其模拟物为代表的多肽和聚合物近年来得到广泛关注. 而分子刷作为一类独特的聚合物也显示 了很多特殊的性能. 我们结合前期研究, 首次将两种开环聚合体系即β-内酰胺开环聚合和N-羧基环内酸酐(NCA)开环聚合体系相结合, 以 β多肽为骨架结构进而通过其氨基功能基团进一步引发NCA开环聚合, 合成了侧链具有多个聚赖氨酸的α/β杂化多肽聚合物分子刷. 这种 新型分子刷对多种MRSA菌株均展现出高效的抗菌活性, 甚至优于万古霉素. 通过扫描电子显微镜(SEM)表征, 揭示了α/β杂化多肽聚合物 分子刷的抗菌机理与宿主防御肽类似, 是通过破坏细菌细胞膜的完整性杀菌. α/β杂化多肽聚合物分子刷高度可调的结构特点和高效的抗 菌活性, 显示了其在抗菌研究和应用中的潜力.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Taubes G. The bacteria fight back. Science, 2008, 321: 356–361

    Article  Google Scholar 

  2. Purrello SM, Garau J, Giamarellos E, et al. Methicillin-resistant Staphylococcus aureus infections: A review of the currently available treatment options. J glob Antimicrobial Resistance, 2016, 7: 178–186

    Article  Google Scholar 

  3. Hancock REW, Sahl HG. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol, 2006, 24: 1551–1557

    Article  Google Scholar 

  4. Boman HG. Antibacterial peptides: Basic facts and emerging concepts. J Intern Med, 2003, 254: 197–215

    Article  Google Scholar 

  5. Zasloff M. Antimicrobial peptides of multicellular organisms. Nature, 2002, 415: 389–395

    Article  Google Scholar 

  6. Nederberg F, Zhang Y, Tan JPK, et al. Biodegradable nanostructures with selective lysis of microbial membranes. Nat Chem, 2011, 3: 409–414

    Article  Google Scholar 

  7. Bai H, Yuan H, Nie C, et al. A supramolecular antibiotic switch for antibacterial regulation. Angew Chem Int Ed, 2015, 54: 13208–13213

    Article  Google Scholar 

  8. Liu K, Liu Y, Yao Y, et al. Supramolecular photosensitizers with enhanced antibacterial efficiency. Angew Chem Int Ed, 2013, 52: 8285–8289

    Article  Google Scholar 

  9. Hu D, Li H, Wang B, et al. Surface-adaptive gold nanoparticles with effective adherence and enhanced photothermal ablation of methicillin-resistant Staphylococcus aureus biofilm. ACS Nano, 2017, 11: 9330–9339

    Article  Google Scholar 

  10. Huang Y, Ding X, Qi Y, et al. Reduction-responsive multifunctional hyperbranched polyaminoglycosides with excellent antibacterial activity, biocompatibility and gene transfection capability. Biomaterials, 2016, 106: 134–143

    Article  Google Scholar 

  11. Wei T, Tang Z, Yu Q, et al. Smart antibacterial surfaces with switchable bacteria-killing and bacteria-releasing capabilities. ACS Appl Mater Interfaces, 2017, 9: 37511–37523

    Article  Google Scholar 

  12. Hancock REW, Haney EF, Gill EE. The immunology of host defence peptides: Beyond antimicrobial activity. Nat Rev Immunol, 2016, 16: 321–334

    Article  Google Scholar 

  13. Yang Y, He P, Wang Y, et al. Supramolecular radical anions triggered by bacteria in situ for selective photothermal therapy. Angew Chem Int Ed, 2017, 56: 16239–16242

    Article  Google Scholar 

  14. Porter EA, Wang X, Lee HS, et al. Non-haemolytic β-amino-acid oligomers. Nature, 2000, 404: 565

    Article  Google Scholar 

  15. Kuroda K, DeGrado WF. Amphiphilic polymethacrylate derivatives as antimicrobial agents. J Am Chem Soc, 2005, 127: 4128–4129

    Article  Google Scholar 

  16. Lienkamp K, Madkour AE, Musante A, et al. Antimicrobial polymers prepared by romp with unprecedented selectivity: A molecular construction kit approach. J Am Chem Soc, 2008, 130: 9836–9843

    Article  Google Scholar 

  17. Song A, Walker SG, Parker KA, et al. Antibacterial studies of cationic polymers with alternating, random, and uniform backbones. ACS Chem Biol, 2011, 6: 590–599

    Article  Google Scholar 

  18. Palermo EF, Sovadinova I, Kuroda K. Structural determinants of antimicrobial activity and biocompatibility in membrane-disrupting methacrylamide random copolymers. Biomacromolecules, 2009, 10: 3098–3107

    Article  Google Scholar 

  19. Jiang Y, Yang X, Zhu R, et al. Acid-activated antimicrobial random copolymers: A mechanism-guided design of antimicrobial peptide mimics. Macromolecules, 2013, 46: 3959–3964

    Article  Google Scholar 

  20. Xiong M, Lee MW, Mansbach RA, et al. Helical antimicrobial polypeptides with radial amphiphilicity. Proc Natl Acad Sci USA, 2015, 112: 13155–13160

    Article  Google Scholar 

  21. Qian Y, Zhang D, Wu Y, et al. The design,synthesis and biological activity study of nylon-3 polymers as mimics of host defense peptides. Acta Polym Sin, 2016, 1300–1311

    Google Scholar 

  22. Liu R, Suárez JM, Weisblum B, et al. Synthetic polymers active against Clostridium difficile vegetative cell growth and spore outgrowth. J Am Chem Soc, 2014, 136: 14498–14504

    Article  Google Scholar 

  23. Liu R, Chen X, Hayouka Z, et al. Nylon-3 polymers with selective antifungal activity. J Am Chem Soc, 2013, 135: 5270–5273

    Article  Google Scholar 

  24. Liu R, Chen X, Falk SP, et al. Nylon-3 polymers active against drug-resistant Candida albicans biofilms. J Am Chem Soc, 2015, 137: 2183–2186

    Article  Google Scholar 

  25. Liu R, Chen X, Chakraborty S, et al. Tuning the biological activity profile of antibacterial polymers via subunit substitution pattern. J Am Chem Soc, 2014, 136: 4410–4418

    Article  Google Scholar 

  26. Tew GN, Scott RW, Klein ML, et al. De novo design of antimicrobial polymers, foldamers, and small molecules: From discovery to practical applications. Acc Chem Res, 2010, 43: 30–39

    Article  Google Scholar 

  27. Li P, Zhou C, Rayatpisheh S, et al. Cationic peptidopolysaccharides show excellent broad-spectrum antimicrobial activities and high selectivity. Adv Mater, 2012, 24: 4130–4137

    Article  Google Scholar 

  28. Niu Y, Padhee S, Wu H, et al. Identification of γ-AApeptides with potent and broad-spectrum antimicrobial activity. Chem Commun, 2011, 47: 12197

    Article  Google Scholar 

  29. Niu Y, Padhee S, Wu H, et al. Lipo-γ-AApeptides as a new class of potent and broad-spectrum antimicrobial agents. J Med Chem, 2012, 55: 4003–4009

    Article  Google Scholar 

  30. Padhee S, Hu Y, Niu Y, et al. Non-hemolytic a-AApeptides as antimicrobial peptidomimetics. Chem Commun, 2011, 47: 9729

    Article  Google Scholar 

  31. Yarlagadda V, Akkapeddi P, Manjunath GB, et al. Membrane active vancomycin analogues: A strategy to combat bacterial resistance. J Med Chem, 2014, 57: 4558–4568

    Article  Google Scholar 

  32. Yarlagadda V, Samaddar S, Paramanandham K, et al. Membrane disruption and enhanced inhibition of cell-wall biosynthesis: A synergistic approach to tackle vancomycin-resistant bacteria. Angew Chem Int Ed, 2015, 54: 13644–13649

    Article  Google Scholar 

  33. Choi H, Chakraborty S, Liu R, et al. Single-cell, time-resolved antimicrobial effects of a highly cationic, random nylon-3 copolymer on live Escherichia coli. ACS Chem Biol, 2016, 11: 113–120

    Article  Google Scholar 

  34. Ding X, Duan S, Ding X, et al. Versatile antibacterial materials: An emerging arsenal for combatting bacterial pathogens. Adv Funct Mater, 2018, 362: 1802140

    Article  Google Scholar 

  35. Su Y, Tian L, Yu M, et al. Cationic peptidopolysaccharides synthesized by ‘click’ chemistry with enhanced broad-spectrum antimicrobial activities. Polym Chem, 2017, 8: 3788–3800

    Article  Google Scholar 

  36. Pranantyo D, Xu LQ, Hou Z, et al. Increasing bacterial affinity and cytocompatibility with four-arm star glycopolymers and antimicrobial a-polylysine. Polym Chem, 2017, 8: 3364–3373

    Article  Google Scholar 

  37. Lu H, Wang J, Lin Y, et al. One-pot synthesis of brush-like polymers via integrated ring-opening metathesis polymerization and polymerization of amino acid N-carboxyanhydrides. J Am Chem Soc, 2009, 131: 13582–13583

    Article  Google Scholar 

  38. Wang J, Lu H, Ren Y, et al. Interrupted helical structure of grafted polypeptides in brush-like macromolecules. Macromolecules, 2015, 44: 8699–8708

    Article  Google Scholar 

  39. Meereboer NL, Terzic I, Saidi S, et al. Two-dimensional controlled syntheses of polypeptide molecular brushes via N-carboxyanhydride ring-opening polymerization and ring-opening metathesis polymerization. ACS Macro Lett, 2017, 6: 1031–1035

    Article  Google Scholar 

  40. Beers KL, Gaynor SG, Matyjaszewski K, et al. The synthesis of densely grafted copolymers by atom transfer radical polymerization. Macromolecules, 1998, 31: 9413–9415

    Article  Google Scholar 

  41. Cheng G, Böker A, Zhang M, et al. Amphiphilic cylindrical core -shell brushes via a “grafting from” process using atrp. Macromolecules, 2001, 34: 6883–6888

    Article  Google Scholar 

  42. Gerle M, Fischer K, Roos S, et al. Main chain conformation and anomalous elution behavior of cylindrical brushes as revealed by GPC/MALLS, light scattering, and SFM. Macromolecules, 1999, 32: 2629–2637

    Article  Google Scholar 

  43. Li Z, Ma J, Cheng C, et al. Synthesis of hetero-grafted amphiphilic diblock molecular brushes and their self-assembly in aqueous medium. Macromolecules, 2010, 43: 1182–1184

    Article  Google Scholar 

  44. Müllner M, Dodds SJ, Nguyen TH, et al. Size and rigidity of cylindrical polymer brushes dictate long circulating properties in vivo. ACS Nano, 2015, 9: 1294–1304

    Article  Google Scholar 

  45. Neugebauer D, Sumerlin BS, Matyjaszewski K, et al. How dense are cylindrical brushes grafted from a multifunctional macroinitiator? Polymer, 2004, 45: 8173–8179

    Article  Google Scholar 

  46. Runge MB, Bowden NB. Synthesis of high molecular weight comb block copolymers and their assembly into ordered morphologies in the solid state. J Am Chem Soc, 2007, 129: 10551–10560

    Article  Google Scholar 

  47. Xia Y, Kornfield JA, Grubbs RH. Efficient synthesis of narrowly dispersed brush polymers via living ring-opening metathesis polymerization of macromonomers. Macromolecules, 2009, 42: 3761–3766

    Article  Google Scholar 

  48. Zheng G, Pan C. Reversible addition-fragmentation transfer polymerization in nanosized micelles formed in situ. Macromolecules, 2006, 39: 95–102

    Article  Google Scholar 

  49. Xia Y, Olsen BD, Kornfield JA, et al. Efficient synthesis of narrowly dispersed brush copolymers and study of their assemblies: The importance of side chain arrangement. J Am Chem Soc, 2009, 131: 18525–18532

    Article  Google Scholar 

  50. Zhang Y, Yin Q, Lu H, et al. Peg-polypeptide dual brush block copolymers: Synthesis and application in nanoparticle surface pegylation. ACS Macro Lett, 2013, 2: 809–813

    Article  Google Scholar 

  51. Gao Q, Yu M, Su Y, et al. Rationally designed dual functional block copolymers for bottlebrush-like coatings: In vitro and in vivo antimicrobial, antibiofilm, and antifouling properties. Acta Biomater, 2017, 51: 112–124

    Article  Google Scholar 

  52. Verduzco R, Li X, Pesek SL, et al. Structure, function, self-assembly, and applications of bottlebrush copolymers. Chem Soc Rev, 2015, 44: 2405–2420

    Article  Google Scholar 

  53. Lu X, Tran TH, Jia F, et al. Providing oligonucleotides with steric selectivity by brush-polymer-assisted compaction. J Am Chem Soc, 2015, 137: 12466–12469

    Article  Google Scholar 

  54. Gao AX, Liao L, Johnson JA. Synthesis of acid-labile peg and pegdoxorubicin-conjugate nanoparticles via brush-first romp. ACS Macro Lett, 2014, 3: 854–857

    Article  Google Scholar 

  55. Gao H, Matyjaszewski K. Synthesis of molecular brushes by “grafting onto” method: combination of ATRP and click reactions. J Am Chem Soc, 2007, 129: 6633–6639

    Article  Google Scholar 

  56. Guo J, Hong H, Chen G, et al. Theranostic unimolecular micelles based on brush-shaped amphiphilic block copolymers for tumortargeted drug delivery and positron emission tomography imaging. ACS Appl Mater Interfaces, 2014, 6: 21769–21779

    Article  Google Scholar 

  57. Hörtz C, Birke A, Kaps L, et al. Cylindrical brush polymers with polysarcosine side chains: A novel biocompatible carrier for biomedical applications. Macromolecules, 2015, 48: 2074–2086

    Article  Google Scholar 

  58. Jin X, Sun P, Tong G, et al. Star polymer-based unimolecular micelles and their application in bio-imaging and diagnosis. Biomaterials, 2018, 178: 738–750

    Article  Google Scholar 

  59. Li H, Liu H, Nie T, et al. Molecular bottlebrush as a unimolecular vehicle with tunable shape for photothermal cancer therapy. Biomaterials, 2018, 178: 620–629

    Article  Google Scholar 

  60. Liao L, Liu J, Dreaden EC, et al. A convergent synthetic platform for single-nanoparticle combination cancer therapy: Ratiometric loading and controlled release of cisplatin, doxorubicin, and camptothecin. J Am Chem Soc, 2014, 136: 5896–5899

    Article  Google Scholar 

  61. Müllner M, Mehta D, Nowell CJ, et al. Passive tumour targeting and extravasation of cylindrical polymer brushes in mouse xenografts. Chem Commun, 2016, 52: 9121–9124

    Article  Google Scholar 

  62. Sowers MA, McCombs JR, Wang Y, et al. Redox-responsive branched-bottlebrush polymers for in vivo MRI and fluorescence imaging. Nat Commun, 2014, 5: 5460

    Article  Google Scholar 

  63. von Erlach T, Zwicker S, Pidhatika B, et al. Formation and characterization of DNA-polymer-condensates based on poly(2-methyl-2-oxazoline) grafted poly(l-lysine) for non-viral delivery of therapeutic DNA. Biomaterials, 2011, 32: 5291–5303

    Article  Google Scholar 

  64. Zeng X, Wang L, Liu D, et al. Poly(l-lysine)-based cylindrical copolypeptide brushes as potential drug and gene carriers. Colloid Polym Sci, 2016, 294: 1909–1920

    Article  Google Scholar 

  65. Liu R, Masters KS, Gellman SH. Polymer chain length effects on fibroblast attachment on nylon-3-modified surfaces. Biomacromolecules, 2012, 13: 1100–1105

    Article  Google Scholar 

  66. Liu R, Chen X, Gellman SH, et al. Nylon-3 polymers that enable selective culture of endothelial cells. J Am Chem Soc, 2013, 135: 16296–16299

    Article  Google Scholar 

  67. Liu R, Chen X, Falk SP, et al. Structure–activity relationships among antifungal nylon-3 polymers: identification of materials active against drug-resistant strains of Candida albicans. J Am Chem Soc, 2014, 136: 4333–4342

    Article  Google Scholar 

  68. Hou Y, Wang Y, Wang R, et al. Harnessing phosphato-platinum bonding induced supramolecular assembly for systemic cisplatin delivery. ACS Appl Mater Interfaces, 2017, 9: 17757–17768

    Article  Google Scholar 

  69. Qian Y, Qi F, Chen Q, et al. Surface modified with a host defense peptide-mimicking ?-peptide polymer kills bacteria on contact with high efficacy. ACS Appl Mater Interfaces, 2018, 10: 15395–15400

    Article  Google Scholar 

  70. Chakraborty S, Liu R, Hayouka Z, et al. Ternary nylon-3 copolymers as host-defense peptide mimics: Beyond hydrophobic and cationic subunits. J Am Chem Soc, 2014, 136: 14530–14535

    Article  Google Scholar 

  71. Zhang D, Zhang S, Ma P, et al. Synthetic peptidyl polymer displaying potent activity against gram positive bacteria. J Funct Polym, 2018, DOI: 10.14133/j.cnki.1008-9357.20180410001

    Google Scholar 

  72. Hovakeemian SG, Liu R, Gellman SH, et al. Correlating antimicrobial activity and model membrane leakage induced by nylon-3 polymers and detergents. Soft Matter, 2015, 11: 6840–6851

    Article  Google Scholar 

Download references

Acknowledgements

This research was supported by the National Natural Science Foundation of China (21574038 and 21774031), the National Natural Science Foundation of China for Innovative Research Groups (51621002), the National Key Research and Development Program of China (2016YFC1100401), the Natural Science Foundation of Shanghai (18ZR1410300), the “Eastern Scholar Professorship” from Shanghai local government (TP2014034), the national special fund for State Key Laboratory of Bioreactor Engineering (2060204), the 1000 Talent Young Scholar program in China, 111 project (B14018), and the program for professor of special appointment at ECUST. The authors thank Research Center of Analysis and Test of East China University of Science and Technology for the help on the characterization. We also thank Prof. Hua Lv and Prof. Lichen Yin for valuable discussions on NCA synthesis and purification.

Author information

Authors and Affiliations

  1. State Key Laboratory of Bioreactor Engineering, Key Laboratory for Ultrafine Materials of Ministry of Education, Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, China

    Danfeng Zhang  (张丹丰), Yuxin Qian  (钱宇芯), Si Zhang  (张思), Pengcheng Ma  (马鹏程), Qiang Zhang  (张强), Ning Shao  (邵宁), Fan Qi  (齐凡), Jiayang Xie  (谢佳洋), Chengzhi Dai  (代承志), Ruiyi Zhou  (周睿毅), Zhongqian Qiao  (乔忠乾), Wenjing Zhang  (张雯静), Sheng Chen  (陈胜) & Runhui Liu  (刘润辉)

Authors
  1. Danfeng Zhang  (张丹丰)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuxin Qian  (钱宇芯)
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Si Zhang  (张思)
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pengcheng Ma  (马鹏程)
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiang Zhang  (张强)
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ning Shao  (邵宁)
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fan Qi  (齐凡)
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jiayang Xie  (谢佳洋)
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chengzhi Dai  (代承志)
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ruiyi Zhou  (周睿毅)
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhongqian Qiao  (乔忠乾)
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wenjing Zhang  (张雯静)
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sheng Chen  (陈胜)
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Runhui Liu  (刘润辉)
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Runhui Liu  (刘润辉).

Additional information

Danfeng Zhang was born in 1992. He received his BSc degree majored in material science and engineering from East China University of Science and Technology (ECUST) in 2018. His research interest is polymeric antimicrobial material.

Runhui Liu obtained BSc in Pharmaceutical Engineering in 2001 at East China University of Science & Technology. He obtained Ph.D in Organic Chemistry 2009 at Purdue University. Afterward, he worked as a postdoc at California Institute of Technology and University of Wisconsin-Madison. In 2014, he took a professor position in the School of Materials Science and Engineering at ECUST. His current research focuses on polypeptide polymers for antimicrobial and tissue engineering applications.

Electronic supplementary material

40843_2018_9351_MOESM1_ESM.pdf

Alpha-Beta Chimeric Polypeptide Molecular Brushes Display Potent Activity Against Superbugs – Methicillin Resistant Staphylococcus aureus

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, D., Qian, Y., Zhang, S. et al. Alpha-beta chimeric polypeptide molecular brushes display potent activity against superbugs-methicillin resistant Staphylococcus aureus. Sci. China Mater. 62, 604–610 (2019). https://doi.org/10.1007/s40843-018-9351-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40843-018-9351-x

Search

Navigation