Intracellular biomass flocculation as a key mechanism of rapid bacterial killing by cationic, amphipathic antimicrobial peptides and peptoids.
Intracellular biomass flocculation as a key mechanism of rapid bacterial killing by cationic, amphipathic antimicrobial peptides and peptoids.
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DOI：
10.1038/s41598-017-16180-0
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发表时间：
2017-12-01
影响因子：
4.6
通讯作者：
Barron AE
中科院分区：
文献类型：
--
作者：
Chongsiriwatana NP;Lin JS;Kapoor R;Wetzler M;Rea JAC;Didwania MK;Contag CH;Barron AE
许多生物体依赖于抗微生物肽（AMP）作为抵抗病原体的第一道防线。一般来说，大多数AMP被认为通过结合并破坏细胞膜来杀死细菌。然而，某些AMP反而似乎抑制生物大分子合成，同时引起较少的膜损伤。尽管对机制的理解还不清楚，但人们对用稳定的合成分子模拟AMP有相当大的兴趣。抗微生物的N-取代的甘氨酸（类肽）寡聚物（“ampetoids”）是螺旋阳离子AMP的结构、功能和机制类似物，其提供广谱抗细菌活性和比肽更好的治疗潜力。在这里，我们通过膜透化，电子显微镜和软X射线断层扫描的定量研究表明，AMP和ampetoids触发广泛和快速的非特异性聚集的细胞内生物大分子，与微生物死亡。我们目前的数据表明，ampetoids是“快速杀手”，在体外和体内迅速聚集细菌核糖体。我们认为细胞内生物质絮凝是阳离子两亲性AMP杀伤的一个关键机制，这可以解释为什么大多数AMP需要微摩尔浓度的活性，显示出对哺乳动物细胞杀死细菌的显着选择性，最后，为什么对AMP的耐药性的发展比对常规抗生素的耐药性不那么普遍。
Many organisms rely on antimicrobial peptides (AMPs) as a first line of defense against pathogens. In general, most AMPs are thought to kill bacteria by binding to and disrupting cell membranes. However, certain AMPs instead appear to inhibit biomacromolecule synthesis, while causing less membrane damage. Despite an unclear understanding of mechanism(s), there is considerable interest in mimicking AMPs with stable, synthetic molecules. Antimicrobial N-substituted glycine (peptoid) oligomers (“ampetoids”) are structural, functional and mechanistic analogs of helical, cationic AMPs, which offer broad-spectrum antibacterial activity and better therapeutic potential than peptides. Here, we show through quantitative studies of membrane permeabilization, electron microscopy, and soft X-ray tomography that both AMPs and ampetoids trigger extensive and rapid non-specific aggregation of intracellular biomacromolecules that correlates with microbial death. We present data demonstrating that ampetoids are “fast killers”, which rapidly aggregate bacterial ribosomes in vitro and in vivo. We suggest intracellular biomass flocculation is a key mechanism of killing for cationic, amphipathic AMPs, which may explain why most AMPs require micromolar concentrations for activity, show significant selectivity for killing bacteria over mammalian cells, and finally, why development of resistance to AMPs is less prevalent than developed resistance to conventional antibiotics.
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影响因子：
3.6
作者：
Contag, CH;Contag, PR;Benaron, DA
通讯作者：
Benaron, DA
影响因子：
--
作者：
Huang, CY;Uno, T;Zuckermann, RN
通讯作者：
Zuckermann, RN
DOI：
10.1016/j.bbamcr.2014.11.006
发表时间：
2015-02-01
影响因子：
5.1
作者：
Gaspar, Diana;Freire, Joao M.;Castanho, Miguel A. R. B.
通讯作者：
Castanho, Miguel A. R. B.
影响因子：
3.7
作者：
Huang W;Seo J;Willingham SB;Czyzewski AM;Gonzalgo ML;Weissman IL;Barron AE
通讯作者：
Barron AE
影响因子：
5.2
作者：
Guilhelmelli F;Vilela N;Albuquerque P;Derengowski Lda S;Silva-Pereira I;Kyaw CM
通讯作者：
Kyaw CM