Department of Chemistry, Thompson Rivers University, 900 McGill Road, Kamloops, BC, Canada V2C 5N3.
Org Biomol Chem. 2010 Apr 7;8(7):1679-87. doi: 10.1039/b921248e. Epub 2010 Feb 11.
In the current study, indolicidin, a known antimicrobial originally isolated from bovine neutrophils, was modified with respect to hydrophobicity and tryptophan content to maximize bioactivity, and minimize cytotoxicity. Since indolicidin contains five tryptophans (very hydrophobic) of its total 13 amino acids, alanine (mildly hydrophobic) was incrementally substituted in its place to generate five novel derivatives with decreasing hydrophobicity. Antimicrobial testing identified two active derivatives with minimum inhibitory concentrations in the 10(-9) g mL(-1) range against Candida albicans, as well as broad-spectrum activity against various other Gram-positive/negative pathogens in the 10(-3)-10(-6) g mL(-1) range. Cytotoxicity testing yielded minimum hemolytic concentrations of approximately 3 x 10(-3) g mL(-1) for both active derivatives, resulting in hemolytic indices of >1.3 x 10(6) (peptide Delta45) and 3.6 x 10(5) (peptide Delta5) (improvements of >33,000-fold and approximately 10,000-fold, respectively, compared to indolicidin). The potent antimicrobial activity and low cytotoxicity of these derivatives show promise as potential antibiotics.
在当前的研究中，源于牛中性粒细胞的抗菌肽 indolicidin 经过修饰以增加其疏水性和色氨酸含量，从而最大化其生物活性，同时最小化其细胞毒性。由于 indolicidin 含有 5 个色氨酸（非常疏水），占其 13 个氨基酸的一半，因此用丙氨酸（中度疏水）逐渐取代它们，生成 5 种疏水性逐渐降低的新型衍生物。抗菌测试确定了两种具有活性的衍生物，其对白色念珠菌的最小抑菌浓度在 10(-9) g mL(-1)范围内，对各种其他革兰氏阳性/阴性病原体的广谱活性在 10(-3)-10(-6) g mL(-1)范围内。细胞毒性测试得出两种活性衍生物的最低溶血浓度约为 3 x 10(-3) g mL(-1)，溶血指数大于 1.3 x 10(6)（肽 Delta45）和 3.6 x 10(5)（肽 Delta5）（与 indolicidin 相比，分别提高了 33,000 倍和 10,000 倍左右）。这些衍生物具有强大的抗菌活性和低细胞毒性，有望成为潜在的抗生素。
