The Disulfide Bond of the Peptide Thanatin Is Dispensible for Its Antimicrobial Activity In Vivo and In Vitro
The Disulfide Bond of the Peptide Thanatin Is Dispensible for Its Antimicrobial Activity In Vivo and In Vitro
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肽 Thanatin 的二硫键对于其体内和体外抗菌活性来说是可有可无的
DOI：
10.1128/aac.00041-16
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发表时间：
2016-07-01
影响因子：
4.9
通讯作者：
Hou, Zheng
中科院分区：
文献类型：
--
作者：
Ma, Bo;Niu, Chao;Hou, Zheng
Thanatin (THA) 显示出有效的抗生素活性，尤其是在体外和体内针对产生超广谱 β-内酰胺酶 (ESBL) 的大肠杆菌，具有最小的溶血毒性和令人满意的血浆稳定性。然而，thanatin的高成本极大地限制了其开发和临床应用。为了降低肽合成的成本，合成了一种称为线性thanatin（L-thanatin）的环状thanatin（C-thanatin）制剂，并在体内和体外评估了其活性。结果显示，C-thanatin 和 L-thanatin 对八种革兰氏阴性菌株和两种革兰氏阳性菌株的 MIC 没有差异。此外，产 ESBL 的大肠杆菌的存活率。大肠杆菌感染的小鼠在以 5 或 10 mg/kg 体重的 C-thanatin 或 L-thanatin 治疗后表现一致。 C-thanatin和L-thanatin在浓度高达256μg/ml时均未表现出对人红细胞(hRBC)和人脐静脉内皮细胞(HUVEC)的毒性。圆二色光谱结果表明L-thanatin的二级结构与C-thanatin极其相似。膜透化和去极化测定表明，C-thanatin 和 L-thanatin 具有相似的透化外膜和内膜以及诱导产 ESBL 大肠杆菌膜去极化的能力。然而，它们都没有引起显着的 HUVEC 膜通透性。这些发现表明，这两种肽对细菌细胞膜具有相似的作用，并且thanatin中的二硫键对于其体内和体外抗菌活性并不是必需的。因此，L-thanatin 是一种有前途的低成本候选肽，用于治疗产 ESBL 的大肠杆菌感染。
Thanatin (THA) displays potent antibiotic activity, especially against extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli both in vitro and in vivo, with minimal hemolytic toxicity and satisfactory stability in plasma. However, the high cost of thanatin significantly limits its development and clinical application. To reduce the cost of peptide synthesis, a formulation of cyclic thanatin (C-thanatin) called linear thanatin (L-thanatin) was synthesized and its activity was evaluated in vivo and in vitro. Results showed that C-thanatin and L-thanatin MICs did not differ against eight Gram-negative and two Gram-positive bacterial strains. Furthermore, the survival rates of ESBL-producing-E. coli-infected mice were consistent after C-thanatin or L-thanatin treatment at 5 or 10 mg/kg of body weight. Neither C-thanatin nor L-thanatin showed toxicity for human red blood cells (hRBCs) and human umbilical vein endothelial cells (HUVECs) at a concentration as high as 256 mu g/ml. Results of circular dichroism spectroscopy indicated that the secondary structure of L-thanatin is extremely similar to that of C-thanatin. Membrane permeabilization and depolarization assays showed that C-thanatin and L-thanatin have similar abilities to permeabilize the outer and inner membranes and to induce membrane depolarization in ESBL-producing E. coli. However, neither of them caused significant HUVEC membrane permeability. These findings indicate that the two peptides have similar effects on bacterial cell membranes and that the disulfide bond in thanatin is not essential for its antimicrobial activities in vivo and in vitro. L-thanatin is thus a promising low-cost peptide candidate for treating ESBL-producing E. coli infections.