STRUCTURE-FUNCTION STUDIES OF AMPHIPHILIC ANTIBACTERIAL PEPTIDES
STRUCTURE-FUNCTION STUDIES OF AMPHIPHILIC ANTIBACTERIAL PEPTIDES
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DOI：
10.1021/jm00061a011
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发表时间：
1993-04-30
影响因子：
7.3
通讯作者：
FRIDKIN, M
中科院分区：
文献类型：
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作者：
BESSALLE, R;GOREA, A;FRIDKIN, M
用固相合成法合成了11个多肽，组成从9到17个氨基酸残基不等，目的是研究两亲性和疏水性、分子大小和电荷分布对抗菌活性的影响。研究发现，由16个和17个氨基酸残基组成的具有高度疏水性(主要来源于Trp或Phe)和亲水性(源于Lys)的多肽分布在相对的两亲性面上，与革兰氏阳性和革兰氏阴性ATCC菌株一起对临床分离的细菌显示出相当强的抗菌活性。然而，这些多肽的溶血能力也是显著的。通过用亮氨酸残基取代色氨酸或苯丙氨酸来降低分子的疏水性，同时保持Lys的碱性贡献，大大降低了溶血活性，仅略微降低了生物活性。由9-10个氨基酸残基组成的具有高度疏水性和碱性的多肽具有抗菌活性，但一般来说，活性低于较大的对应多肽。通过用亮氨酸残基取代短肽的所有色氨酸残基，活性大大降低。圆二色谱研究和抗菌试验表明，螺旋含量很低的短肽失去了两亲性，仍然具有较高的生物活性。这一观察结果，再加上由于它们的尺寸小而不能跨越细菌的外脂双层的事实，可能表明长链相对于短链多肽的作用机制不同。
The synthesis of 11 peptides, ranging in composition from 9 to 17 amino acid residues, by solid-phase methodology was accomplished with the purpose of studying how the amphiphilic and hydrophobic character, the size of the molecule, and the charge distribution modulate the antibacterial activity. It was found that peptides composed of 16 and 17 amino acid residues, with high hydrophobic (mainly due to Trp or Phe) and hydrophilic (due to Lys) character distributed along opposite amphiphilic faces, showed considerable antibacterial activity against clinically isolated bacteria together with Gram positive and Gram negative ATCC bacterial strains. However, the hemolytic capacity of the peptides was also significant. Decreasing the hydrophobic character of the molecule by replacing Trp or Phe with Leu residues while maintaining the basic contribution of Lys drastically reduced the hemolytic activity and only slightly decreased the bioactivity. Peptides composed of 9-10 amino acid residues with high hydrophobic and basic nature possess antibacterial activity but, in general, are less active than the larger counterpart peptides. By replacing all Trp residues of a short peptide by Leu residues, the activity was considerably reduced. Circular dichroism studies and antibacterial assays showed that shorter peptides with very low helical content, and thus deprived of amphiphilic character, still have appreciable bioactivity. This observation, coupled with the fact that due to their small size they cannot span the bacterial outer lipid bilayer, may suggest different mechanisms of action for long-chain vis-a-vis short-chain peptides.