Chen Sheng, Luo Zhengjie, Zhou Min, Xiao Ximian, Cong Zihao, Xie Jiayang, Wu Yueming, Zhang Haodong, Zhao Xuebin, Song Gonghua, Liu Runhui
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, P. R. China.
Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Engineering Research Center for Biomedical Materials of Ministry of Education, Key Laboratory of Specially Functional Polymeric Materials and Related Technology, East China University of Science and Technology, Shanghai 200237, P. R. China.
J Mater Chem B. 2025 May 7;13(18):5315-5326. doi: 10.1039/d5tb00184f.
The high mortality of drug-resistant bacterial infections, especially those caused by multidrug-resistant Gram-negative pathogens, highlights an urgent demand for promising antimicrobial strategies. Host defense peptide (HDP)-mimicking poly-β-peptides have demonstrated significant potential in combating drug-resistant bacterial infections, with their antimicrobial activity closely dependent on their side-chain structures. However, the restricted structural diversity of poly-β-peptides necessitates efficient synthetic methods to expand their diversity, particularly positively charged side-chain structures. This study presents a water-tolerant approach that facilitates the controllable synthesis of poly-β-peptides with different chain lengths and structurally diverse side chains, including primary amines, tertiary amines, as well as alkyl, aryl, and methoxy groups. This approach serves as an HDP-mimicking discovery platform to obtain the optimal poly-β-peptide, AOcHNL, which exhibits broad-spectrum antibacterial activity and high selectivity against drug-resistant bacteria. The antibacterial mechanism studies reveal that AOcHNL disrupts the membrane of Gram-negative bacteria. evaluations substantiate the therapeutic potential of AOcHNL in treating drug-resistant bacterial infections with no observable toxicity. This study underscores the potential of this convenient synthetic strategy as a promising platform for developing antimicrobial poly-β-peptides to combat the growing threat of drug-resistant bacterial infections.
耐药细菌感染，尤其是由多重耐药革兰氏阴性病原体引起的感染，死亡率很高，这凸显了对有前景的抗菌策略的迫切需求。模仿宿主防御肽（HDP）的聚-β-肽在对抗耐药细菌感染方面已显示出巨大潜力，其抗菌活性与其侧链结构密切相关。然而，聚-β-肽有限的结构多样性需要高效的合成方法来扩大其多样性，特别是带正电荷的侧链结构。本研究提出了一种耐水方法，该方法有助于可控合成具有不同链长和结构多样侧链的聚-β-肽，包括伯胺、叔胺以及烷基、芳基和甲氧基。该方法作为一个模仿HDP的发现平台，用于获得最佳聚-β-肽AOcHNL，其具有广谱抗菌活性且对耐药细菌具有高选择性。抗菌机制研究表明，AOcHNL破坏革兰氏阴性菌的细胞膜。评估证实了AOcHNL在治疗耐药细菌感染方面的治疗潜力，且无明显毒性。本研究强调了这种便捷合成策略作为开发抗菌聚-β-肽以对抗日益严重的耐药细菌感染威胁的有前景平台的潜力。
