Bradshaw Jeremy
Department of Preclinical Veterinary Sciences, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, Scotland, UK.
BioDrugs. 2003;17(4):233-40. doi: 10.2165/00063030-200317040-00002.
Many different types of organisms use antimicrobial peptides, typically 20-40 amino acids in length, for defence against infection. Most are capable of rapidly killing a wide range of microbial cells. They have been classified according to their active structures into six extensive groups. It is not yet clear how these peptides kill bacterial cells, but it is widely believed that some cationic antimicrobial peptides kill by disrupting bacterial membranes, allowing the free exchange of intra- and extra-cellular ions. The selectivity of these peptides appears to relate to differences between the external membranes of prokaryotic and eukaryotic cells. The action of the peptides may involve the formation of 'barrel-stave' or 'torroidal' pores, the introduction of packing defects in the membrane phospholipids, or large-scale disruption of the membrane by a very dense aggregation of parallel-oriented peptide, called the 'carpet mechanism'. Antimicrobial peptides are attractive candidates for clinical development because of their selectivity, their speed of action and because bacteria may not easily develop resistance against them. Some antimicrobial peptides are already in clinical and commercial use, including ambicin (nisin), polymixin B and gramicidin S. There have been several attempts at developing peptides to make them more suitable for clinical use. For those peptides that act against bacterial membranes, it is possible to differentiate between those structural features that contribute to the specificity of initial membrane binding and those that contribute to the subsequent breach of membrane integrity. The design of novel antimicrobial peptides would necessitate the optimisation of multiple parameters, a problem that has proved difficult to solve. Potential problems to be overcome include high production costs, toxicity against eukaryotic cells, susceptibility to proteolytic degradation and the development of allergies to the peptides. Biosynthesis, using recombinant DNA techniques, could make commercial-scale synthesis feasible but the peptides are usually lethal to the micro-organisms used to produce them. Proteolytic degradation can be reduced by modifying the peptides to contain nonstandard amino acids, or by restricting the use of peptides to topical applications. The problem of sensitisation could be overcome by the use of our own natural antibiotics to prevent or treat infections. Despite early hopes that bacteria would not easily develop resistance to antimicrobial peptides, it is clear that some strains of bacteria already have.
许多不同类型的生物体利用抗菌肽（通常长度为20 - 40个氨基酸）来抵御感染。大多数抗菌肽能够迅速杀死多种微生物细胞。它们已根据其活性结构被分为六大类。目前尚不清楚这些肽是如何杀死细菌细胞的，但人们普遍认为一些阳离子抗菌肽通过破坏细菌膜来杀死细菌，从而使细胞内和细胞外离子能够自由交换。这些肽的选择性似乎与原核细胞和真核细胞外膜之间的差异有关。肽的作用可能涉及形成“桶板”或“环形”孔，在膜磷脂中引入堆积缺陷，或者通过平行排列的肽的非常密集聚集（称为“地毯机制”）对膜进行大规模破坏。抗菌肽因其选择性、作用速度以及细菌可能不容易对其产生耐药性而成为临床开发的有吸引力的候选物。一些抗菌肽已经在临床和商业中使用，包括乳链菌肽、多粘菌素B和短杆菌肽S。已经有几次尝试开发更适合临床使用的肽。对于那些作用于细菌膜的肽，可以区分有助于初始膜结合特异性的结构特征和有助于随后破坏膜完整性的结构特征。新型抗菌肽的设计需要优化多个参数，这是一个已证明难以解决的问题。需要克服的潜在问题包括高生产成本、对真核细胞的毒性、易受蛋白水解降解以及对肽产生过敏反应。使用重组DNA技术进行生物合成可以使商业规模的合成可行，但这些肽通常对用于生产它们的微生物具有致死性。通过修饰肽使其包含非标准氨基酸，或者将肽的使用限制在局部应用，可以减少蛋白水解降解。可以通过使用我们自身的天然抗生素来预防或治疗感染来克服致敏问题。尽管早期希望细菌不容易对抗菌肽产生耐药性，但很明显一些细菌菌株已经产生了耐药性。
