The Lipopeptide Antibiotic Friulimicin B Inhibits Cell Wall Biosynthesis through Complex Formation with Bactoprenol Phosphate
The Lipopeptide Antibiotic Friulimicin B Inhibits Cell Wall Biosynthesis through Complex Formation with Bactoprenol Phosphate
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DOI：
10.1128/aac.01040-08
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发表时间：
2009-04-01
影响因子：
4.9
通讯作者：
Sahl, H. -G.
中科院分区：
文献类型：
--
作者：
Schneider, T.;Gries, K.;Sahl, H. -G.
弗留利霉素B是一种天然存在的环状脂肽，由放线菌弗留利游动放线菌（Actinoplanes friuliensis）产生，对革兰氏阳性病原体（包括多重耐药菌株）具有优异的活性。它由一个大环十肽核心和一个脂尾组成，由一个环外氨基酸相互连接。弗留利米星是水溶性和两亲性的，具有总体负电荷。两亲性在Ca 2+的存在下增强，这也是抗微生物活性所不可或缺的。弗留利霉素与达托霉素具有相同的理化性质，达托霉素被认为通过在细胞质膜中形成孔来杀死革兰氏阳性菌。尽管弗留利霉素与达托霉素具有相同的结构和效力特征，但我们发现弗留利霉素具有独特的作用模式，并通过确定的靶标作用，严重影响革兰氏阳性菌的细胞包膜。我们发现弗鲁利米星通过与磷酸巴托肾上腺素载体C-55-P形成Ca 2+依赖性复合物来中断细胞壁前体周期，所述磷酸巴托肾上腺素载体C-55-P不被使用中的任何其他抗生素靶向。由于C-55-P也作为磷壁酸生物合成和胶囊形成的载体，很可能弗鲁利米星阻断了功能性革兰氏阳性细胞包膜所必需的多种途径。
Friulimicin B is a naturally occurring cyclic lipopeptide, produced by the actinomycete Actinoplanes friuliensis, with excellent activity against gram-positive pathogens, including multidrug-resistant strains. It consists of a macrocyclic decapeptide core and a lipid tail, interlinked by an exocyclic amino acid. Friulimicin is water soluble and amphiphilic, with an overall negative charge. Amphiphilicity is enhanced in the presence of Ca2+, which is also indispensable for antimicrobial activity. Friulimicin shares these physicochemical properties with daptomycin, which is suggested to kill gram-positive bacteria through the formation of pores in the cytoplasmic membrane. In spite of the fact that friulimicin shares features of structure and potency with daptomycin, we found that friulimicin has a unique mode of action and severely affects the cell envelope of gram-positive bacteria, acting via a defined target. We found friulimicin to interrupt the cell wall precursor cycle through the formation of a Ca2+-dependent complex with the bactoprenol phosphate carrier C-55-P, which is not targeted by any other antibiotic in use. Since C-55-P also serves as a carrier in teichoic acid biosynthesis and capsule formation, it is likely that friulimicin blocks multiple pathways that are essential for a functional gram-positive cell envelope.