Zou Pengfei, Liu Jiao, Li Xinyu, Yaseen Muhammad, Yao Jiahui, Liu Lingling, Luo Lujun, Wang Hui, Shi Xinghua, Li Zhiping, Sun Tongyi, Gao Yuanyuan, Gao Chunsheng, Li Li Li
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing100190, China.
State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing100850, China.
ACS Nano. 2022 Dec 27;16(12):20545-20558. doi: 10.1021/acsnano.2c07251. Epub 2022 Nov 14.
The extensive spread of multidrug resistance to Gram-negative bacteria has become a huge threat to human health, where peptide-based antibacterial agents have emerged as a powerful star weapon. Here we report a lipopeptide () constructed nanomicelle with a different antibacterial mechanism of membrane curvature modulation, which induced dynamic membrane fission resulting in acceleration and enhancement of antibacterial activity to clinically isolated ESKAPE strains, including multidrug-resistant (MDR) pathogens. The minimum inhibitory concentration was reduced to 2-10 μM, and the minimum duration for killing was shortened to less than an hour by . This is an improvement over antimicrobial peptides and traditional antibiotics, such as ciprofloxacin and tetracycline, significantly enhancing antibacterial activity for MDR, and we observed no acquisition of resistance for one month. This accelerated germicidal mechanism was attributed to multitargeting with lipopolysaccharides, phosphoethanolamine, phosphatidylglycerol, and cardiolipin, and the synergetic interactions induced a high curvature of the bacterial membrane, which facilitated simultaneously efficient damage to both inner and outer membrane. The effectively prolonged the lifetime of myositis mice with MDR and pneumonia mice with through a hepatic metabolism with ignorable toxicity. This study provides critical information for the fabrication of lipopeptide-based nano-antibiotics for the efficient control of intractable MDR caused by Gram-negative pathogens.
革兰氏阴性菌多重耐药性的广泛传播已对人类健康构成巨大威胁，基于肽的抗菌剂已成为一种强大的明星武器。在此，我们报道了一种通过具有膜曲率调节不同抗菌机制构建的脂肽纳米胶束，其可诱导动态膜裂变，从而加速并增强对临床分离的ESKAPE菌株（包括多重耐药病原体）的抗菌活性。最小抑菌浓度降低至2-10μM，杀菌最短时间缩短至不到一小时。这相较于抗菌肽和传统抗生素（如环丙沙星和四环素）有了改进，显著增强了对多重耐药菌的抗菌活性，并且我们观察到一个月内未出现耐药性。这种加速杀菌机制归因于与脂多糖、磷酸乙醇胺、磷脂酰甘油和心磷脂的多靶点作用，协同相互作用诱导细菌膜产生高曲率，从而同时促进对内膜和外膜的有效损伤。该纳米胶束通过肝脏代谢有效延长了多重耐药性肌炎小鼠和肺炎小鼠的寿命，且毒性可忽略不计。本研究为制备基于脂肽的纳米抗生素以有效控制革兰氏阴性病原体引起的顽固性多重耐药性提供了关键信息。
