|
|||||
|
|
Structural Element of Vitamin U-Mimicking Antibacterial Polypeptide with Ultrahigh Selectivity for Effectively Treating MRSA Infections |
|
| Authors: | Zhenyan Zhang Xiaodan Wang Jiaying Liu Huawei Yang Haoyu Tang Jing Li Shifang Luan Jinghua Yin Lei Wang Hengchong Shi |
| Affiliation: | 1. School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026 P. R. China State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 P. R. China These authors contributed equally to this work. Contribution: Conceptualization (lead), Data curation (lead), Formal analysis (lead), Methodology (lead), Writing - original draft (lead);2. School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026 P. R. China State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 P. R. China These authors contributed equally to this work. Contribution: Conceptualization (lead), Data curation (equal), Methodology (equal);3. School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026 P. R. China Contribution: Formal analysis (supporting), Methodology (equal), Visualization (equal);4. State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 P. R. China;5. Institute of Functional Nano & Soft Materials (FUNSOM), Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Suzhou, 215123 P. R. China Contribution: Writing - review & editing (supporting);6. State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun, Changchun, 130022 P. R. China Contribution: Software (equal);7. School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026 P. R. China State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 P. R. China Contribution: Funding acquisition (equal);8. State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 P. R. China Contribution: Funding acquisition (supporting);9. School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026 P. R. China |
| Abstract: | Antimicrobial peptides (AMPs) exhibit mighty antibacterial properties without inducing drug resistance. Achieving much higher selectivity of AMPs towards bacteria and normal cells has always been a continuous goal to be pursued. Herein, a series of sulfonium-based polypeptides with different degrees of branching and polymerization were synthesized by mimicking the structure of vitamin U. The polypeptide, G2-PM-1H+, shows both potent antibacterial activity and the highest selectivity index of 16000 among the reported AMPs or peptoids (e.g., the known index of 9600 for recorded peptoid in “Angew. Chem. Int. Ed., 2020, 59, 6412.”), which can be attributed to the high positive charge density of sulfonium and the regulation of hydrophobic chains in the structure. The antibacterial mechanisms of G2-PM-1H+ are primarily ascribed to the interaction with the membrane, production of reactive oxygen species (ROS), and disfunction of ribosomes. Meanwhile, altering the degree of alkylation leads to selective antibacteria against either gram-positive or gram-negative bacteria in a mixed-bacteria model. Additionally, both in vitro and in vivo experiments demonstrated that G2-PM-1H+ exhibited superior efficacy against methicillin-resistant Staphylococcus aureus (MRSA) compared to vancomycin. Together, these results show that G2-PM-1H+ possesses high biocompatibility and is a potential pharmaceutical candidate in combating bacteria significantly threatening human health. |
| Keywords: | Antibacterial Mechanism Antibacterial Selectivity Antimicrobial Polypeptides Hemocompatibility Sulfonium |