Antibacterial and detoxifying activity of NZ17074 analogues with multi-layers of selective antimicrobial actions against Escherichia coli and Salmonella enteritidis.
Antibacterial and detoxifying activity of NZ17074 analogues with multi-layers of selective antimicrobial actions against Escherichia coli and Salmonella enteritidis.
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NZ17074类似物的抗菌和解毒活性，对大肠杆菌和肠炎沙门氏菌具有多层选择性抗菌作用
DOI：
10.1038/s41598-017-03664-2
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发表时间：
2017-06-13
影响因子：
4.6
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Yang N;Liu X;Teng D;Li Z;Wang X;Mao R;Wang X;Hao Y;Wang J
NZ17074(N1)是从蚯蚓中分离得到的Arenicin-3衍生物，具有较强的抗菌活性和细胞毒性。为了降低其细胞毒性，设计了7个不同结构的N1类似物，通过改变它们的二硫键、疏水性或电荷。“火箭”类似物-N_2和“风筝”类似物-N_6具有较强的活性，对RAW264.7细胞的细胞毒性低于N_1。核磁共振谱表明，N1、N2和N6采用由一个或两个二硫键稳定的β-Sheet结构。N_2和N_6对肠炎沙门氏菌的内外膜有通透性，但对肠炎链球菌的内膜没有通透性。N_2和N_6分别诱导大肠杆菌和肠炎沙门氏菌细胞周期停滞于I期和R期。在大肠杆菌和肠炎链霉菌中，这两种多肽分别抑制18.7-43.8%的DNA/RNA/细胞壁合成和5.7-61.8%的DNA/RNA/蛋白质合成。经这两种多肽处理后，大肠杆菌细胞崩解，呈丝状，肠炎链球菌细胞形态完整。体重剂量在2.57.5 mg/kg的N_2和N_6可提高腹膜炎和内毒素血症小鼠的存活率，降低血清IL-6、IL-1β和肿瘤坏死因子-α水平，保护小鼠免受内毒素肺损伤。这些数据表明，N_2和N_6通过多个选择性作用，有望成为新型抗微生物和抗内毒素的双功能候选多肽。
NZ17074 (N1), an arenicin-3 derivative isolated from the lugworm, has potent antibacterial activity and is cytotoxic. To reduce its cytotoxicity, seven N1 analogues with different structures were designed by changing their disulfide bonds, hydrophobicity, or charge. The “rocket” analogue-N2 and the “kite” analogue-N6 have potent activity and showed lower cytotoxicity in RAW264.7 cells than N1. The NMR spectra revealed that N1, N2, and N6 adopt β-sheet structures stabilized by one or two disulfide bonds. N2 and N6 permeabilized the outer/inner membranes of E. coli, but did not permeabilize the inner membranes of S. enteritidis. N2 and N6 induced E. coli and S. enteritidis cell cycle arrest in the I-phase and R-phase, respectively. In E. coli and in S. enteritidis, 18.7–43.8% of DNA/RNA/cell wall synthesis and 5.7–61.8% of DNA/RNA/protein synthesis were inhibited by the two peptides, respectively. Collapsed and filamentous E. coli cells and intact morphologies of S. enteritidis cells were observed after treatment with the two peptides. Body weight doses from 2.5–7.5 mg/kg of N2 and N6 enhanced the survival rate of peritonitis- and endotoxemia-induced mice; reduced the serum IL-6, IL-1β and TNF-α levels; and protected mice from lipopolysaccharide-induced lung injury. These data indicate that N2 and N6, through multiple selective actions, may be promising dual-function candidates as novel antimicrobial and anti-endotoxin peptides.