Elucidation of the antimicrobial mechanism of mutacin 1140
Elucidation of the antimicrobial mechanism of mutacin 1140
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DOI：
10.1021/bi701262z
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发表时间：
2008-03-11
期刊：
影响因子：
2.9
通讯作者：
Orugunty, Ravi S.
中科院分区：
文献类型：
--
作者：
Smith, Leif;Hasper, Hester;Orugunty, Ravi S.
Mutacin 1140 和乳链菌肽 A 是属于羊毛硫抗生素家族的肽类抗生素。乳链菌肽 A 和突变蛋白 1140（脂质 II 结合结构域）的 N 端环 A 和 B 具有许多结构和序列相似性。乳链菌肽 A 与脂质 II 结合，从而破坏细胞壁合成并形成跨膜孔。在这方面，人们对 Mutacin 1140 知之甚少。我们使用细菌模拟膜系统进行了基于荧光的研究。结果表明，突变蛋白 1140 复合物中的脂质 II 单体的排列方式与乳链菌肽 A 复合物中的排列方式不同。复合物形成中的这些差异可能归因于以下事实：乳链菌肽 A 使用脂质 II 形成独特的孔复合物，而突变蛋白 1140 不在该膜系统中形成孔。进一步的实验表明，突变蛋白1440-脂质II和乳链菌肽A-脂质II复合物非常稳定并且能够承受彼此的竞争。使用对 Mutacin 1140 敏感的鼠链球菌菌株进行的跨膜电位实验表明，即使浓度比最低抑制浓度 (MIC) 高 8 倍，mutacin 1140 也不会在该菌株中形成孔。通过电子显微镜观察到 mutacin 1140 和乳链菌肽 A 的圆形复合物，为这些抗生素的横向组装机制提供了直接证据。 Mutacin 1140确实在另一种常用的人工细菌膜系统中表现出膜破坏功能，并且其破坏活性通过增加阴离子磷脂的量而增强。
Mutacin 1140 and nisin A are peptide antibiotics that belong to the lantibiotic family. N-Terminal rings A and B of nisin A and mutacin 1140 (lipid II-binding domain) share many structural and sequence similarities. Nisin A binds lipid II and thus disrupts cell wall synthesis and also forms transmembrane pores. Very little is known about mutacin 1140 in this regard. We performed fluorescence-based studies using a bacteria-mimetic membrane system. The results indicated that lipid II monomers are arranged differently in the mutacin 1140 complex than in the nisin A complex. These differences in complex formation may be attributed to the fact that nisin A uses lipid II to form a distinct pore complex, while mutacin 1140 does not form pores in this membrane system. Further experiments demonstrated that the mutacin 1440-lipid II and nisin A-lipid II complexes are very stable and capable of withstanding competition from each other. Transmembrane electrical potential experiments using a Streptococcus rattus strain, which is sensitive to mutacin 1140, demonstrated that mutacin 1140 does not form pores in this strain even at a concentration 8 times higher than the minimum inhibitory concentration (MIC). Circular complexes of mutacin 1140 and nisin A were observed by electron microscopy, providing direct evidence for a lateral assembly mechanism for these antibiotics. Mutacin 1140 did exhibit a membrane disruptive function in another commonly used artificial bacterial membrane system, and its disruptive activity was enhanced by increasing amounts of anionic phospholipids.