Ribosomally Synthesized Thiopeptide Antibiotics Targeting Elongation Factor Tu
Ribosomally Synthesized Thiopeptide Antibiotics Targeting Elongation Factor Tu
复制标题
DOI：
10.1021/ja900488a
复制
发表时间：
2009-04-29
影响因子：
15
通讯作者：
Krastel, Philipp
中科院分区：
文献类型：
--
作者：
Morris, Rowan P.;Leeds, Jennifer A.;Krastel, Philipp
我们确定了thiomuracins，一个新的家庭的硫肽产生的稀有放线菌属细菌型为Nonomuraea物种，通过筛选抑制细菌病原体金黄色葡萄球菌的生长。硫肽是一类由噻唑修饰并由中心六元杂环系统限定的大环、高度修饰的肽。挖掘硫肽生产菌株的基因组揭示了这类抗生素难以捉摸的生物合成途径。硫肽是染色体编码的、核糖体合成的蛋白质，并且用于生产硫代穆拉星和相关硫肽GE 2270 A的基因簇的分离揭示了成熟所需的翻译后机制。硫代穆拉菌素的靶标被鉴定为细菌延伸因子Tu（EF-Tu）。除了有效地抑制未被市售人类治疗剂利用的靶标之外，硫代穆拉菌素具有选择抗生素耐药性的低倾向，并且在临床使用中不赋予对抗生素的可测量的交叉耐药性。
We identified the thiomuracins, a novel family of thiopeptides produced by a rare-actinomycete bacterium typed as a Nonomuraea species, via a screen for inhibition of growth of the bacterial pathogen Staphylococcus aureus. Thiopeptides are a class of macrocyclic, highly modified peptides that are decorated by thiazoles and defined by a central six-membered heterocyclic ring system. Mining the genomes of thiopeptide-producing strains revealed the elusive biosynthetic route for this class of antibiotics. The thiopeptides are chromosomally encoded, ribosomally synthesized proteins, and isolation of gene clusters for production of thiomuracin and the related thiopeptide GE2270A revealed the post-translational machinery required for maturation. The target of the thiomuracins was identified as bacterial Elongation Factor Tu (EF-Tu). In addition to potently inhibiting a target that is unexploited by marketed human therapeutics, the thiomuracins have a low propensity for selecting for antibiotic resistance and confer no measurable cross-resistance to antibiotics in clinical use.