New insights into the mechanism of action of lantibiotics -: diverse biological effects by binding to the same molecular target
New insights into the mechanism of action of lantibiotics -: diverse biological effects by binding to the same molecular target
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DOI：
10.1093/jac/46.1.1
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发表时间：
2000-07-01
影响因子：
5.2
通讯作者：
Sahl, HG
中科院分区：
文献类型：
--
作者：
Brötz, H;Sahl, HG
主要文章肽聚糖合成分析，mersacidin和actagardine块转糖基化，酶的反应，其中肽聚糖的糖链聚合。11（图2a）。为了研究这种抑制的分子基础，转糖基酶的底物，膜结合的肽聚糖前体十一异戊二烯基二磷酰基-N-乙酰胞壁酸-（五肽）-N-乙酰葡糖胺（脂质II）从细菌膜纯化。结合研究表明，mersacidin和actagardine形成一个紧密的复合物与脂质II的万古霉素，脂质II复合物有很大的不同，但同样阻止转糖基酶进入其底物。8. A型羊毛硫抗生素的情况更为复杂。Ramseier 12首次发现了乳链菌肽杀菌机制的线索，他观察到紫外线吸收物质从处理过的细菌中流出，并提出了类似洗涤剂的效果。随后的研究表明，向易感细胞中加入A型羊毛硫抗生素会导致放射性标记物（如铷、氨基酸和核苷酸）从细胞质中泄漏，并导致膜电位立即消失。6，13在用A型羊毛硫醚抗生素处理后，所有生物合成过程立即停止，这与B型羊毛硫醚抗生素对肽聚糖生物合成的选择性抑制形成鲜明对比。这些结果有力地表明，A型羊毛硫抗生素破坏细胞质膜的完整性，虽然实验证据排除了广义的洗涤剂样增溶作用。[14]为了研究膜紊乱的性质，随后对各种生理和人工膜系统进行了研究。在对黑色脂质膜（由选定的磷脂制成的人工双层）的研究中，当施加外部电压时，A型羊毛硫醚抗生素在膜上形成独特的、寿命短的孔。15核磁共振数据表明，在与磷脂胶束接触时，A型羊毛硫抗生素采用这样的构象，即阳离子氨基酸的侧链延伸到肽的一侧并与带负电荷的磷脂头部基团相互作用，而疏水残基在相对侧排列并浸入膜核心中。16，17基于这些结构数据和对细胞质膜囊泡、人工脂质体和胶束的各种研究，提出了孔形成过程的以下模型。18，19孔的形成是由阳离子A型羊毛硫抗生素对带负电荷的磷脂的静电吸引引发的。[20]在插入膜中时，羊毛硫抗生素被认为垂直于膜定向，并且由于它们在这种重排过程中不会失去与磷脂的接触，它们使双层弯曲并迫使瞬时孔打开（图2b）。这一过程的驱动力被认为是由膜电位提供的，因为它是由膜电位产生的。
Leading articles peptidoglycan synthesis assays, mersacidin and actagardine block transglycosylation, the enzyme reaction by which the sugar chains of the peptidoglycan are polymerized. 11 (Figure 2a). In order to investigate the molecular basis for this inhibition, the substrate of the transglycosylase, the membrane-bound peptidoglycan precursor undecaprenyldiphosphoryl-N-acetylmuramic acid–(pentapeptide)-N-acetylglucosamine (lipid II) was purified from bacterial membranes. Binding studies revealed that mersacidin and actagardine form a tight complex with lipid II which differs greatly from the vancomycin–lipid II complex, but equally blocks access of the transglycosylase to its substrate. 8 In the case of the type A lantibiotics, the situation is more complex. First hints on the bactericidal mechanism of nisin were obtained by Ramseier, 12 who observed efflux of UV-absorbing material from treated bacteria and suggested a detergent-like effect. Subsequent studies demonstrated that the addition of type A lantibiotics to susceptible cells leads to the leakage of radiolabelled markers, such as rubidium, amino acids and nucleotides, from the cytoplasm and to the immediate dissipation of the membrane potential. 6, 13 Upon treatment with type A lantibiotics, all biosynthetic processes cease instantly, which is in clear contrast to the selective inhibition of peptidoglycan biosynthesis by the type B lantibiotics. These results strongly indicated that type A lantibiotics destroy the integrity of the cytoplasmic membrane, although experimental evidence excluded a generalized detergent-like solubilization. 14 Investigations with a variety of physiological and artificial membrane systems followed in order to investigate the nature of the membrane disorder. In studies with black lipid membranes (artificial bilayers made of selected phospholipids), type A lantibiotics formed distinct, short-lived pores across the membrane when external voltage was applied. 15 Nuclear magnetic resonance data indicate that, upon contact with phospholipid micelles, type A lantibiotics adopt a conformation such that the side chains of cationic amino acids extend to one side of the peptide and interact with the negatively charged phospholipid head groups, whereas the hydrophobic residues align themselves at the opposite side and become immersed in the membrane core. 16, 17 On the basis of such structural data and of various studies with cytoplasmic membrane vesicles, artificial liposomes and micelles, the following model was proposed for the pore-forming process. 18, 19 Pore formation is initiated by the electrostatic attraction of the cationic type A lantibiotics to the negatively charged phospholipids. 20 Upon insertion into the membrane the lantibiotics are presumed to orient themselves perpendicularly to the membrane and, since they do not lose contact with the phospholipids in the course of this rearrangement, they bend the bilayer and force a transient pore to open (Figure 2b). The driving force for this process is thought to be provided by the membrane potential, as it is generated by