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首页> 外文期刊>Combinatorial Chemistry & High Throughput Screening >Molecular Mechanisms of Membrane Perturbation by Antimicrobial Peptides and the Use of Biophysical Studies in the Design of Novel Peptide Antibiotics
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Molecular Mechanisms of Membrane Perturbation by Antimicrobial Peptides and the Use of Biophysical Studies in the Design of Novel Peptide Antibiotics

机译：抗菌肽对膜的扰动分子机制及生物物理研究在新型肽抗生素设计中的应用

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摘要

Antibiotic resistant bacterial strains represent a global health problem with a strong social andneconomic impact. Thus, there is an urgent need for the development of antibiotics with novel mechanisms ofnaction. There is currently an extensive effort to understand the mode of action of antimicrobial peptides whichnare considered as one alternative to classical antibiotics. The main advantage of this class of substances, whennconsidering bacterial resistance, is that they rapidly, within minutes, kill bacteria. Antimicrobial peptides cannbe found in every organism and display a wide spectrum of activity. Hence, the goal is to engineer peptidesnwith an improved therapeutic index, i.e. high efficacy and target specificity. For the rational design of suchnnovel antibiotics it is essential to elucidate the molecular mechanism of action. Biophysical studies have beennperformed using to a large extent membrane model systems demonstrating that there are distinctive differentnmechanisms of bacterial killing by antimicrobial peptides. One can distinguish between peptides thatnpermeabilize and/or disrupt the bacterial cell membrane and peptides that translocate through the cellnmembrane and interact with a cytosolic target. Lantibiotics exhibit specific mechanisms, e.g. binding to lipidnII, a precursor of the peptidoglycan layer, either resulting in membrane rupture by pore formation or preventingncell wall biosynthesis. The classical models of membrane perturbation, pore formation and carpet mechanism,nare discussed and related to other mechanisms that may lead to membrane dysfunction such as formation ofnlipid-peptide domains or membrane disruption by formation of non-lamellar phases. Emphasis is on the role ofnmembrane lipid composition in these processes and in the translocation of antimicrobial peptides.
机译：抗生素抗药性菌株代表着具有广泛的社会和经济影响的全球健康问题。因此，迫切需要开发具有新的作用机制的抗生素。当前正在广泛地努力理解抗微生物肽的作用方式，其被认为是经典抗生素的一种替代物。当考虑细菌抵抗力时，这类物质的主要优点是它们可以在数分钟内迅速杀死细菌。抗菌肽无法在每个生物体中找到，并具有广泛的活性。因此，目的是设计具有改善的治疗指数，即高功效和靶标特异性的肽。为了合理设计此类新型抗生素，必须阐明其作用的分子机制。已经在很大程度上使用膜模型系统进行了生物物理研究，证明了抗菌肽对细菌的杀灭具有不同的机理。可以区分能透化和/或破坏细菌细胞膜的肽和易位穿过细胞膜并与胞质靶标相互作用的肽。羊毛硫抗生素表现出特定的机制，例如与脂质聚糖（肽聚糖层的前体）结合，导致孔形成而导致膜破裂或阻止细胞壁生物合成。没有讨论膜扰动，孔形成和毛毯机制的经典模型，并且与其他可能导致膜功能障碍的机制有关，例如形成脂肽域或由于形成非层状相而破坏了膜。重点是膜脂质成分在这些过程中以及在抗菌肽的转运中的作用。

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