Microbial natural products comprise diverse architectures that are generated by equally diverse biosynthetic strategies. In peptide natural products, amino acid sidechains are frequently used as sites of modification to generate macrocyclic motifs. Backbone amide groups, among the most stable of biological moieties, are rarely used for this purpose. Here we report the discovery and biosynthesis of bicyclostreptins—peptide natural products from Streptococcus spp. with an unprecedented structural motif consisting of a macrocyclic β-ether and a heterocyclic sp³–sp³ linkage between a backbone amide nitrogen and an adjacent α-carbon. Both reactions are installed, in that order, by two radical S-adenosylmethionine (RaS) metalloenzymes. Bicyclostreptins are produced at nM concentrations and are potent growth regulation agents in Streptococcus thermophilus. Our results add a distinct and unusual chemotype to the growing family of ribosomal peptide natural products, expand the already impressive catalytic scope of RaS enzymes, and provide avenues for further biological studies in human-associated streptococci.

微生物天然产物包含不同的结构，这些结构由同样多样化的生物合成策略产生。在肽天然产物中，氨基酸侧链经常被用作修饰位点以产生大环基序。主链酰胺基团是最稳定的生物部分之一，很少用于此目的。在这里，我们报告了双环链菌素的发现和生物合成——来自链球菌属的肽天然产物。具有前所未有的结构基序，由大环 β-醚和杂环sp ³ – sp ^3组成骨架酰胺氮和相邻的α-碳之间的连接。两种反应均由两种自由基 S-腺苷甲硫氨酸 (RaS) 金属酶按此顺序进行。Bicyclostreptins 以 nM 浓度产生，是嗜热链球菌的有效生长调节剂。我们的研究结果为不断增长的核糖体肽天然产物家族增添了一种独特且不寻常的化学型，扩大了 RaS 酶已经令人印象深刻的催化范围，并为人类相关链球菌的进一步生物学研究提供了途径。