Darveau R P, Blake J, Seachord C L, Cosand W L, Cunningham M D, Cassiano-Clough L, Maloney G
Immune Science Group, Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
J Clin Invest. 1992 Aug;90(2):447-55. doi: 10.1172/JCI115880.
A peptide (C13) corresponding to the last 13 amino acids of the carboxyl terminus of human platelet factor IV was found to be antibacterial. Amino acid substitutions predicted to disrupt either the amphipathic or alpha-helical nature of C13 rendered the peptide inactive. Antibacterial activity was demonstrated in normal human serum on bacteria which had been previously exposed to low levels of cefepime, a beta-lactam antibiotic. Peptide analogues were examined for more potent antibacterial activity in an antibacterial assay that employed normal human serum and low levels of cefepime. A peptide analogue (C18G) with 80-fold more antibacterial activity than C13 was identified. Studies in C8-deficient sera confirmed an essential role of human serum complement for optimal antibacterial activity. Additional studies showed low levels of cefepime, although not essential, enhanced the antibacterial activity of C18G. Animal protection experiments demonstrated that either peptide C18G or an analogue with all D amino acids (C18X) significantly increased the survival of neutropenic mice when coadministered with a low level of cefepime. This work has resulted in the identification of a new group of antibacterial peptides.
一种与人类血小板因子IV羧基末端最后13个氨基酸相对应的肽（C13）被发现具有抗菌作用。预测会破坏C13两亲性或α螺旋性质的氨基酸取代会使该肽失去活性。在正常人血清中，对先前暴露于低水平头孢吡肟（一种β-内酰胺抗生素）的细菌显示出抗菌活性。在一项使用正常人血清和低水平头孢吡肟的抗菌试验中，对肽类似物进行了更有效抗菌活性的检测。鉴定出一种抗菌活性比C13高80倍的肽类似物（C18G）。在C8缺陷血清中的研究证实了人血清补体对最佳抗菌活性的重要作用。进一步的研究表明，低水平的头孢吡肟虽然不是必需的，但可增强C18G的抗菌活性。动物保护实验表明，当与低水平的头孢吡肟共同给药时，肽C18G或一种全D氨基酸的类似物（C18X）可显著提高中性粒细胞减少小鼠的存活率。这项工作已导致鉴定出一组新的抗菌肽。
