An alternatingly amphiphilic, resistance-resistant antimicrobial oligoguanidine with dual mechanisms of action

Chen, Zhiyong1,2; Zhou, Cailing1,2,4; Xu, Yangfan1,2,4; Wen, Kang1,2; Song, Junfeng1,2; Bai, Silei1,2; Wu, Chenxuan1,2; Huang, Wei1,2; Cai, Qingyun1,2; Zhou, Kai5,6; Wang, Hui7; Wang, Yingjie3; Feng, Xinxin1,2; Bai, Yugang1,2

2021-08-01

10.1016/j.biomaterials.2021.120858

BIOMATERIALS   影响因子和分区

0142-9612

1878-5905

The increasing number of infections caused by multi-drug resistance (MDR) bacteria is an omen of a new global challenge. As one of the countermeasures under development, antimicrobial peptides (AMPs) and AMP mimics have emerged as a new family of antimicrobial agents with high potential, due to their low resistance generation rate and effectiveness against MDR bacterial strains resulted from their membrane-disrupting mechanism of action. However, most reported AMPs and AMP mimics have facially amphiphilic structures, which may lead to undesired self-aggregation and non-specific binding, as well as increased cytotoxicity toward mammalian cells, all of which put significant limits on their applications. Here, we report an oligomer with the size of short AMPs, with both hydrophobic carbon chain and cationic groups placed on its backbone, giving an alternatingly amphiphilic structure that brings better selectivity between mammalian and bacterial cell membranes. In addition, the oligomer shows affinity toward DNA, thus it can utilize bacterial DNA located in the vulnerable nucleoid as the second drug target. Benefiting from these designs, the oligomer shows higher therapeutic index and synergistic effect with other antibiotics, while its low resistance generation rate and effectiveness on multidrug resistant bacterial strains can be maintained. We demonstrate that this alternatingly amphiphilic, DNAbinding oligomer is not only resistance-resistant, but is also able to selectively eliminate bacteria at the presence of mammalian cells. Importantly, the oligomer exhibits good in vivo activity: it cleans all bacteria on Caenorhabditis elegans without causing apparent toxicity, and significantly improves the survival rate of mice with severely infected wounds in a mice excision wound model study.

Antibiotic resistance DNA binding Membrane disruption Amphiphilicity Antibiotic sensitization

SCI ; EI

英语

其他

National Natural Science Foundation of China[21877033,21807031,21874038] ; Shenzhen Municipal Science and Technology Innovation Commission[KQTD20170330155106581]

Engineering ; Materials Science

Engineering, Biomedical ; Materials Science, Biomaterials

WOS:000681662300001

ELSEVIER SCI LTD

MATERIALS SCIENCE

Web of Science

1.Hunan Univ, Hunan Prov Key Lab Biomacromol Chem Biol, State Key Lab Chem Biosensing & Chemometr, Inst Chem Biol & Nanomed, Changsha 410082, Hunan, Peoples R China
2.Hunan Univ, Sch Chem & Chem Engn, Changsha 410082, Hunan, Peoples R China
3.Shenzhen Bay Lab, Inst Syst & Phys Biol, Shenzhen 518055, Guangdong, Peoples R China
4.Hunan Univ, Sch Biol, Changsha 410082, Hunan, Peoples R China
5.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen Inst Resp Dis, Shenzhen Peoples Hosp, Shenzhen 518035, Guangdong, Peoples R China
6.Jinan Univ, Clin Med Coll 2, Shenzhen Peoples Hosp, Shenzhen 518020, Guangdong, Peoples R China
7.Peking Univ Peoples Hosp, Dept Clin Labs, Beijing 100044, Peoples R China

Chen, Zhiyong,Zhou, Cailing,Xu, Yangfan,et al. An alternatingly amphiphilic, resistance-resistant antimicrobial oligoguanidine with dual mechanisms of action[J]. BIOMATERIALS,2021,275.

Chen, Zhiyong.,Zhou, Cailing.,Xu, Yangfan.,Wen, Kang.,Song, Junfeng.,...&Bai, Yugang.(2021).An alternatingly amphiphilic, resistance-resistant antimicrobial oligoguanidine with dual mechanisms of action.BIOMATERIALS,275.

Chen, Zhiyong,et al."An alternatingly amphiphilic, resistance-resistant antimicrobial oligoguanidine with dual mechanisms of action".BIOMATERIALS 275(2021).