模拟宿主防御肽的尼龙3抗菌聚合物结构设计、合成及活性研究

钱宇芯; 张丹丰; 武月铭; 陈琦; 刘润辉

doi:10.11777/j.issn1000-3304.2016.16194

您当前的位置：

首页 >

文章列表页 >

模拟宿主防御肽的尼龙3抗菌聚合物结构设计、合成及活性研究

专论 | 更新时间：2021-03-19

- 模拟宿主防御肽的尼龙3抗菌聚合物结构设计、合成及活性研究
- The Design,Synthesis and Biological Activity Study of Nylon-3 Polymers as Mimics of Host Defense Peptides
- 高分子学报 2016年第10期页码：1300-1311
- 作者机构：
  
  1.华东理工大学生物反应器工程国家重点实验室上海 200237
  2.华东理工大学教育部医用生物材料工程研究中心上海 200237
  3.华东理工大学材料科学与工程学院上海 200237
- 作者简介：
  
  刘润辉,E-mail:rliu@ecust.edu.cn Run-hui Liu,E-mail:rliu@ecust.edu.cn
- 基金信息：
- DOI：10.11777/j.issn1000-3304.2016.16194
  中图分类号：
- 纸质出版日期：2016-10，
  
  收稿日期：2016-6-7，
  
  修回日期：2016-7-2，
扫描看全文
钱宇芯, 张丹丰, 武月铭, 陈琦, 刘润辉. 模拟宿主防御肽的尼龙3抗菌聚合物结构设计、合成及活性研究[J]. 高分子学报, 2016,(10):1300-1311.

Qian Yu-xin, Zhang Dan-feng, Wu Yue-ming, Chen Qi, Liu Run-hui. The Design,Synthesis and Biological Activity Study of Nylon-3 Polymers as Mimics of Host Defense Peptides[J]. Acta Polymerica Sinica, 2016,(10):1300-1311.
钱宇芯, 张丹丰, 武月铭, 陈琦, 刘润辉. 模拟宿主防御肽的尼龙3抗菌聚合物结构设计、合成及活性研究[J]. 高分子学报, 2016,(10):1300-1311. DOI： 10.11777/j.issn1000-3304.2016.16194.

Qian Yu-xin, Zhang Dan-feng, Wu Yue-ming, Chen Qi, Liu Run-hui. The Design,Synthesis and Biological Activity Study of Nylon-3 Polymers as Mimics of Host Defense Peptides[J]. Acta Polymerica Sinica, 2016,(10):1300-1311. DOI： 10.11777/j.issn1000-3304.2016.16194.

摘要

微生物感染一直是人类健康的严峻挑战，传统抗生素几乎不可避免地使微生物产生耐药性，因此亟待开发既对耐药细菌、真菌有活性，又不易使微生物产生耐药性的新型抗菌剂.宿主防御肽（host defense peptide，HDP）几乎存在于各种生命形式中并表现出广谱抗菌活性和不易使微生物产生耐药性的特点，近年来作为对抗微生物耐药性的新途径被广泛研究.为解决HDP自身稳定性差（容易被蛋白酶水解）的缺点，多个研究组相继开展HDP模拟物的研究，希望在改善抗菌剂稳定性的同时保持抗菌活性.尼龙3聚合物（

-多肽）是模拟HDP的一类代表性抗菌聚合物.尼龙3聚合物通常由一个亲水性/正电荷亚基和一个疏水性亚基通过不同比例组合来模拟HDP的2个关键性结构特点：正电荷和两亲性结构.通过优化端基基团和聚合物长度、变化亚基的化学结构、探索优化的亲水性/正电荷与疏水性亚基组合以及调节亚基在聚合物中的比例，发现了对多个耐药菌菌株具有高活性和高选择性的尼龙3聚合物.尼龙3对细菌营养细胞和稳定的孢子都显示了活性，同时尼龙3也对游离真菌细胞和真菌生物膜都表现出选择性抗菌活性.这些发现提示了尼龙3对抗微生物耐药性的潜力以及尼龙3作为新型抗菌剂的可能应用.

Abstract

Microbial infection is always a serious challenge to human health

especially with the emergency of drug-resistant bacteria and fungi such as methicillin-resistant

S.aureus

(MRSA) and fluconazole-resistant

C.albicans.

Conventional antibiotics are inevitably susceptible to antimicrobial resistance

therefore

it is urgent to develop new type of antimicrobial agents that are active against existing drug-resistant bacteria and fungi and are less susceptible for pathogens to develop antimicrobial resistance.Host defense peptide (HDP) that exists naturally in almost all forms of lives and demonstrates broad spectrum antimicrobial activity and low susceptibility to antimicrobial resistance has been widely studied in recent years to develop new types of antimicrobial agents in combating antimicrobial resistance.The application of HDP itself is limited by its low stability or high susceptibility to proteolysis and its only moderate antimicrobial activity compared to clinical antimicrobial drugs.Intense work has been done in developing mimics of HDP to acquire improved stability and optimized antimicrobial activity.Nylon-3 polymers (poly-

-peptides) belong to one of the representative HDP-mimicking antimicrobial polymers.Nylon-3 polymers are generally composed by one hydrophilic/cationic subunit and one hydrophobic subunit at varied ratio to mimic two key structure characteristics of HDP: positive charges and amphiphilicity.By optimizing the terminal functional group and polymer length

varying chemical structure of subunits

exploring the optimized subunit combination

and carefully tuning ratio of subunits within polymer chains

we are able to find nylon-3 polymers that demonstrate potent and selective activities against multiple strains of drug-resistant bacteria including MRSA.Using

C.difficile

as a model

nylon-3 displays dual functions by killing

C.difficile

vegetative cells directly and preventing the outgrowth of spore to vegetative cells.Nylon-3 also demonstrates potent activity against multiple strains of fungi

including the most common human fungal pathogen

C.albicans

that are resistant to fluconazole and

even amphotericin B

.When applied to complicated and robust biofilm system

nylon-3 can efficiently inhibit the formation of fungal biofilms and kill persister cells within mature fungal biofilms.It is noteworthy that neither bacteria nor fungi display antimicrobial resistance against nylon-3.These findings imply the potential of nylon-3 polymers to battle with antimicrobial resistance and their possible application as novel antimicrobial agents for variable applications.

关键词

微生物耐药性宿主防御肽尼龙3抗细菌抗真菌

Keywords

Antimicrobial resistanceHDPNylon-3AntibacterialAntifungal

references

O¸Neill J. Rev Antimicrob Resist,2014.http://amr-review.org/Publicationshttp://amr-review.org/Publications

M Zasloff . . Nature , 2002 . 415 ( 6870 ): 389 - 395 . DOI:10.1038/415389ahttp://doi.org/10.1038/415389a.

R E W Hancock , H G Sahl . . Nat Biotechnol , 2006 . 24 ( 12 ): 1551 - 1557 . DOI:10.1038/nbt1267http://doi.org/10.1038/nbt1267.

G N Tew , D H Liu , B Chen , R J Doerksen , J Kaplan , P J Carroll , M L Klein , W F DeGrado . . P Natl Acad Sci USA , 2002 . 99 ( 8 ): 5110 - 5114 . DOI:10.1073/pnas.082046199http://doi.org/10.1073/pnas.082046199.

B P Mowery , S E Lee , D A Kissounko , R F Epand , R M Epand , B Weisblum , S S Stahl , S H Gellman . . J Am Chem Soc , 2007 . 129 ( 50 ): 15474 - 15476 . DOI:10.1021/ja077288dhttp://doi.org/10.1021/ja077288d.

D Wade , A Boman , B Wahlin , C M Drain , D Andreu , H G Boman , R B Merrifield . . Proc Natl Acad Sci USA , 1990 . 87 ( 12 ): 4761 - 4765 . DOI:10.1073/pnas.87.12.4761http://doi.org/10.1073/pnas.87.12.4761.

Y Hamuro , J P Schneider , W F DeGrado . . J Am Chem Soc , 1999 . 121 ( 51 ): 12200 - 12201 . DOI:10.1021/ja992728phttp://doi.org/10.1021/ja992728p.

E A Porter , X F Wang , H S Lee , B Weisblum , S H Gellman . . Nature , 2000 . 404 ( 6778 ): 565 - 565 . DOI:10.1038/35007145http://doi.org/10.1038/35007145.

M A Gelman , B Weisblum , D M Lynn , S H Gellman . . Org Lett , 2004 . 6 ( 4 ): 557 - 560 . DOI:10.1021/ol036341+http://doi.org/10.1021/ol036341+.

E F Palermo , I Sovadinova , K Kuroda . . Biomacromolecules , 2009 . 10 ( 11 ): 3098 - 3107 . DOI:10.1021/bm900784xhttp://doi.org/10.1021/bm900784x.

K Kuroda , W F DeGrado . . J Am Chem Soc , 2005 . 127 ( 12 ): 4128 - 4129 . DOI:10.1021/ja044205+http://doi.org/10.1021/ja044205+.

Y Q Wang , J J Xu , Y H Zhang , H S Yan , K L Liu . . Macromol Biosci , 2011 . 11 ( 11 ): 1499 - 1504.

Y J Jiang , X Yang , R Zhu , K Hu , W W Lan , F Wu , L H Yang . . Macromolecules , 2013 . 46 ( 10 ): 3959 - 3964 . DOI:10.1021/ma400484bhttp://doi.org/10.1021/ma400484b.

G N Tew , K Lienkamp , A E Madkour , A Musante , C F Nelson , K Nusslein . . J Am Chem Soc , 2008 . 130 ( 30 ): 9836 - 9843 . DOI:10.1021/ja801662yhttp://doi.org/10.1021/ja801662y.

F Nederberg , Y Zhang , J P K Tan , K J Xu , H Y Wang , C Yang , S J Gao , X D Guo , K Fukushima , L J Li , J L Hedrick , Y Y Yang . . Nat Chem , 2011 . 3 ( 5 ): 409 - 414 . DOI:10.1038/nchem.1012http://doi.org/10.1038/nchem.1012.

B P Mowery , A H Lindner , B Weisblum , S S Stahl , S H Gellman . . J Am Chem Soc , 2009 . 131 ( 28 ): 9735 - 9745 . DOI:10.1021/ja901613ghttp://doi.org/10.1021/ja901613g.

R Liu , X Chen , S Chakraborty , J J Lemke , Z Hayouka , C Chow , R A Welch , B Weisblum , K S Masters , S H Gellman . . J Am Chem Soc , 2014 . 136 ( 11 ): 4410 - 4418 . DOI:10.1021/ja500367uhttp://doi.org/10.1021/ja500367u.

R Liu , X Chen , S P Falk , K S Masters , B Weisblum , S H Gellman . . J Am Chem Soc , 2015 . 137 ( 6 ): 2183 - 2186 . DOI:10.1021/ja512567yhttp://doi.org/10.1021/ja512567y.

R Liu , X Chen , S P Falk , B P Mowery , A J Karlsson , B Weisblum , S P Palecek , K S Masters , S H Gellman . . J Am Chem Soc , 2014 . 136 ( 11 ): 4333 - 4342 . DOI:10.1021/ja500036rhttp://doi.org/10.1021/ja500036r.

R Liu , J M Suarez , B Weisblum , S H Gellman , S M McBride . . J Am Chem Soc , 2014 . 136 ( 41 ): 14498 - 14504 . DOI:10.1021/ja506798ehttp://doi.org/10.1021/ja506798e.

R H Liu , X Y Chen , Z Hayouka , S Chakraborty , S P Falk , B Weisblum , K S Masters , S H Gellman . . J Am Chem Soc , 2013 . 135 ( 14 ): 5270 - 5273 . DOI:10.1021/ja4006404http://doi.org/10.1021/ja4006404.

S Chakraborty , R Liu , Z Hayouka , X Chen , J Ehrhardt , Q Lu , E Burke , Y Yang , B Weisblum , G C Wong , K S Masters , S H Gellman . . J Am Chem Soc , 2014 . 136 ( 41 ): 14530 - 14535 . DOI:10.1021/ja507576ahttp://doi.org/10.1021/ja507576a.

S Chakraborty , R H Liu , J J Lemke , Z Hayouka , R A Welch , B Weisblum , K S Masters , S H Gellman . . Acs Macro Lett , 2013 . 2 ( 8 ): 753 - 756 . DOI:10.1021/mz400239rhttp://doi.org/10.1021/mz400239r.

R Liu , K Z Vang , P K Kreeger , S H Gellman , K S Masters . . J Biomed Mater Res A , 2012 . 100 ( 10 ): 2750 - 2759.

R H Liu , X Y Chen , S H Gellman , K S Masters . . J Am Chem Soc , 2013 . 135 ( 44 ): 16296 - 16299 . DOI:10.1021/ja408634ahttp://doi.org/10.1021/ja408634a.

R H Liu , K S Masters , S H Gellman . . Biomacromolecules , 2012 . 13 ( 4 ): 1100 - 1105 . DOI:10.1021/bm201847nhttp://doi.org/10.1021/bm201847n.

V Nadithe , R Liu , B A Killinger , S Movassaghian , N H Kim , A B Moszczynska , K S Masters , S H Gellman , O M Merkel . . Mol Pharm , 2015 . 12 ( 2 ): 362 - 374 . DOI:10.1021/mp5004724http://doi.org/10.1021/mp5004724.

J H K D A Zhang , S E Lee , S H Gellman , S S Stahl . . J Am Chem Soc , 2009 . 131 ( 4 ): 1589 - 1597 . DOI:10.1021/ja8069192http://doi.org/10.1021/ja8069192.

G D Brown , D W Denning , N A Gow , S M Levitz , M G Netea , T C White . . Sci Transl Med , 2012 . 4 ( 165 ): 165r .

H Choi , S Chakraborty , R Liu , S H Gellman , J C Weisshaar . . ACS Chem Biol , 2016 . 11 ( 1 ): 113 - 120 . DOI:10.1021/acschembio.5b00547http://doi.org/10.1021/acschembio.5b00547.

S G Hovakeemian , R Liu , S H Gellman , H Heerklotz . . Soft Matter , 2015 . 11 ( 34 ): 6840 - 6851 . DOI:10.1039/C5SM01521Ahttp://doi.org/10.1039/C5SM01521A.

更多指标>

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

暂无数据