Designed symmetrical β-hairpin peptides for treating multidrug-resistant salmonella typhimurium infections.
Designed symmetrical β-hairpin peptides for treating multidrug-resistant salmonella typhimurium infections.
复制标题
DOI：
10.1016/j.ejmech.2022.114769
复制
发表时间：
2022-09
影响因子：
6.7
通讯作者：
Zhi Ma;Dong Zhang;Ziyi Cheng;Yandong Niu;L. Kong;Zhaoxin Lu;X. Bie
中科院分区：
文献类型：
--
作者：
Zhi Ma;Dong Zhang;Ziyi Cheng;Yandong Niu;L. Kong;Zhaoxin Lu;X. Bie
多重耐药沙门氏菌病的迅速出现和流行缺乏有效的治疗方法，这导致了流行性健康问题，并刺激了具有新作用模式的抗菌药物的开发。本研究通过将Leucocin-A的β-转角与重复的疏水性和阳离子性氨基酸序列相结合，合成了10个短的对称性β-发夹肽。其中WK 2（（WK）2CTKSGC（KW）2）对沙门氏菌细胞的选择性最好，而对巨噬细胞和红细胞的选择性最差。荧光测量和显微镜观察反映WK 2通过膜溶解机制发挥其抗菌活性。此外，β-发夹肽可以与内毒素（LPS）结合并抑制LPS诱导的RAW 264. 7细胞中促炎细胞因子的产生，表明其具有有效的抗炎活性。体内实验还表明，WK 2可降低肝脏和脾脏中沙门氏菌的负荷，减轻沙门氏菌引起的炎症，并保持肠粘膜表面的完整性。最终，结果强调WK 2是一种有前途的治疗剂，可以预防人类和动物的多重耐药鼠伤寒沙门氏菌感染。
The rapid emergence and prevalence of multidrug-resistant salmonellosis lack effective therapies, which causes epidemic health problems and stimulates the development of antimicrobials with novel modes of action. In this research, 10 short symmetricalβ-hairpin peptides are synthesized by combining theβ-turn of Leucocin-A with recurring hydrophobic and cationic amino acid sequences. Those designed peptides exhibited potent antibacterial activities against drug-susceptible and drug-resistantSalmonella.One of the 10 peptides, WK2 ((WK)2CTKSGC(KW)2), displayed best cell selectivity towardsSalmonellacells over macrophages and erythrocytes in a co-culture model. Fluorescent measurements and microscopic observations reflected that WK2 exerted its antimicrobial activity through a membrane-lytic mechanism. Moreover, theβ-hairpin peptides can bind to endotoxin (LPS) and suppress the production of LPS-induced proinflammatory cytokines in RAW264.7 cells, indicating as a potent anti-inflammatory activity. The preliminaryin vivostudies can also demonstrate that WK2 decreased loads ofSalmonellain the liver and spleen, mitigatedSalmonella-caused inflammation and maintained the integrity of intestinal mucosal surfaces. Ultimately, the results highlight that WK2 is a promising therapeutic agent to prevent multidrug-resistantS.Typhimurium infections in humans and animals.