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.
Article PDF
References
Taubes G. The bacteria fight back. Science, 2008, 321: 356–361
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
Hancock REW, Sahl HG. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol, 2006, 24: 1551–1557
Boman HG. Antibacterial peptides: Basic facts and emerging concepts. J Intern Med, 2003, 254: 197–215
Zasloff M. Antimicrobial peptides of multicellular organisms. Nature, 2002, 415: 389–395
Nederberg F, Zhang Y, Tan JPK, et al. Biodegradable nanostructures with selective lysis of microbial membranes. Nat Chem, 2011, 3: 409–414
Bai H, Yuan H, Nie C, et al. A supramolecular antibiotic switch for antibacterial regulation. Angew Chem Int Ed, 2015, 54: 13208–13213
Liu K, Liu Y, Yao Y, et al. Supramolecular photosensitizers with enhanced antibacterial efficiency. Angew Chem Int Ed, 2013, 52: 8285–8289
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
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
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
Hancock REW, Haney EF, Gill EE. The immunology of host defence peptides: Beyond antimicrobial activity. Nat Rev Immunol, 2016, 16: 321–334
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
Porter EA, Wang X, Lee HS, et al. Non-haemolytic β-amino-acid oligomers. Nature, 2000, 404: 565
Kuroda K, DeGrado WF. Amphiphilic polymethacrylate derivatives as antimicrobial agents. J Am Chem Soc, 2005, 127: 4128–4129
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
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
Palermo EF, Sovadinova I, Kuroda K. Structural determinants of antimicrobial activity and biocompatibility in membrane-disrupting methacrylamide random copolymers. Biomacromolecules, 2009, 10: 3098–3107
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
Xiong M, Lee MW, Mansbach RA, et al. Helical antimicrobial polypeptides with radial amphiphilicity. Proc Natl Acad Sci USA, 2015, 112: 13155–13160
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
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
Liu R, Chen X, Hayouka Z, et al. Nylon-3 polymers with selective antifungal activity. J Am Chem Soc, 2013, 135: 5270–5273
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
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
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
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
Niu Y, Padhee S, Wu H, et al. Identification of γ-AApeptides with potent and broad-spectrum antimicrobial activity. Chem Commun, 2011, 47: 12197
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
Padhee S, Hu Y, Niu Y, et al. Non-hemolytic a-AApeptides as antimicrobial peptidomimetics. Chem Commun, 2011, 47: 9729
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
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
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
Ding X, Duan S, Ding X, et al. Versatile antibacterial materials: An emerging arsenal for combatting bacterial pathogens. Adv Funct Mater, 2018, 362: 1802140
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
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
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
Wang J, Lu H, Ren Y, et al. Interrupted helical structure of grafted polypeptides in brush-like macromolecules. Macromolecules, 2015, 44: 8699–8708
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
Beers KL, Gaynor SG, Matyjaszewski K, et al. The synthesis of densely grafted copolymers by atom transfer radical polymerization. Macromolecules, 1998, 31: 9413–9415
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
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
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
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
Neugebauer D, Sumerlin BS, Matyjaszewski K, et al. How dense are cylindrical brushes grafted from a multifunctional macroinitiator? Polymer, 2004, 45: 8173–8179
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
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
Zheng G, Pan C. Reversible addition-fragmentation transfer polymerization in nanosized micelles formed in situ. Macromolecules, 2006, 39: 95–102
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
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
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
Verduzco R, Li X, Pesek SL, et al. Structure, function, self-assembly, and applications of bottlebrush copolymers. Chem Soc Rev, 2015, 44: 2405–2420
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
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
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
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
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
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
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
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
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
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
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
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
Liu R, Masters KS, Gellman SH. Polymer chain length effects on fibroblast attachment on nylon-3-modified surfaces. Biomacromolecules, 2012, 13: 1100–1105
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
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
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
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
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
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
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
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
Corresponding author
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
About this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40843-018-9351-x