Antibacterial properties and mode of action of a short acyl-lysyl oligomer.
Antibacterial properties and mode of action of a short acyl-lysyl oligomer.
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短酰基-赖氨酰低聚物的抗菌特性和作用方式。
DOI：
10.1128/aac.00010-09
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发表时间：
2009
影响因子：
4.9
通讯作者：
Mor,Amram
中科院分区：
文献类型：
--
作者：
Zaknoon,Fadia;Sarig,Hadar;Rotem,Shahar;Livne,Liran;Ivankin,Andrey;Gidalevitz,David;Mor,Amram
我们研究了寡酰基赖氨酸（OAK）NC 12 -2β12的效力、选择性和作用模式，最近有人建议其代表保留非溶血性抗菌特性的最短OAK序列。针对一组48种细菌菌株的生长抑制试验证实，NC 12 -2β 12对革兰氏阳性菌具有强效活性，同时表现出可忽略不计的溶血，最高可达MIC的至少100倍。有趣的是，NC 12 -2β 12表现出抑菌作用模式，不像先前描述的OAK是杀菌的并且基本上仅对革兰氏阴性细菌有活性。与模型磷脂膜结合的各种实验的结果与细胞毒性实验的结果相关性良好，并为观察到的活性特征提供了合理的解释。因此，用模型双层进行的表面等离子体共振实验显示，对模拟葡萄球菌质膜的膜成分具有高亲和力（总体亲和力常数[Kapp]，3.7 × 106 M −1），而对模拟大肠杆菌红细胞质膜的亲和力明显较低。用模拟质膜外小叶的模型Langmuir单层进行的额外插入等温线和落射荧光显微镜实验证明了NC 12 -2β 12优先插入高度阴离子膜。最后，我们提供了机制的研究，支持这样的观点，即抑菌作用导致一个相对缓慢的过程，涉及离散泄漏的小溶质，如细胞内ATP的质膜透化。总的来说，这些数据表明短OAK是新抗菌化合物的潜在来源，这些化合物可以选择性地影响革兰氏阳性菌的生长，同时避免与裂解化合物相关的潜在不良反应。
We investigated the potency, selectivity, and mode of action of the oligo-acyl-lysine (OAK) NC12-2β12, which was recently suggested to represent the shortest OAK sequence that retains nonhemolytic antibacterial properties. A growth inhibition assay against a panel of 48 bacterial strains confirmed that NC12-2β12exerted potent activity against gram-positive bacteria while exhibiting negligible hemolysis up to at least 100 times the MIC. Interestingly, NC12-2β12demonstrated a bacteriostatic mode of action, unlike previously described OAKs that were bactericidal and essentially active against gram-negative bacteria only. The results of various experiments with binding to model phospholipid membranes correlated well with those of the cytotoxicity experiments and provided a plausible explanation for the observed activity profile. Thus, surface plasmon resonance experiments performed with model bilayers revealed high binding affinity to a membrane composition that mimicked the plasma membrane of staphylococci (global affinity constant[Kapp], 3.7 × 106M−1) and significantly lower affinities to mimics ofEscherichia colior red blood cell cytoplasmic membranes. Additional insertion isotherms and epifluorescence microscopy experiments performed with model Langmuir monolayers mimicking the outer leaflet of plasma membranes demonstrated the preferential insertion of NC12-2β12into highly anionic membranes. Finally, we provide mechanistic studies in support of the view that the bacteriostatic effect resulted from a relatively slow process of plasma membrane permeabilization involving discrete leakage of small solutes, such as intracellular ATP. Collectively, the data point to short OAKs as a potential source for new antibacterial compounds that can selectively affect the growth of gram-positive bacteria while circumventing potential adverse effects linked to lytic compounds.