Merochlorins A–D, Cyclic Meroterpenoid Antibiotics Biosynthesized in Divergent Pathways with Vanadium-Dependent Chloroperoxidases

Meroterpenoids are mixed polyketide-terpenoid natural products with a broad range of biological activities. Herein, we present the structures of four new meroterpenoid antibiotics, merochlorins A–D, produced by the marine bacterium Streptomyces sp. strain CNH-189, which possess novel chemical skeletons unrelated to known bacterial agents. Draft genome sequencing, mutagenesis, and heterologous biosynthesis in the genome-minimized model actinomycete Streptomyces coelicolor provided the 57.6 kb merochlorin gene cluster that contains two genes encoding rare bacterial vanadium-dependent haloperoxidase (VHPO) genes. Pathway expression of two different fosmid clones that differ largely by the presence or absence of the VHPO gene mcl40 resulted in the differential biosynthesis of merochlorin C, suggesting that Mcl40 catalyzes an unprecedented 15-membered chloronium-induced macrocyclization reaction converting merochlorin D to merochlorin C.杂萜类（Meroterpenoids）化合物是一类混合聚酮-萜类天然产物，具备广泛的生物活性。本研究报道了由海洋放线菌链霉菌属（Streptomyces sp.）菌株CNH-189产生的四种新型杂萜类抗生素——氯杂菌素A-D（merochlorins A–D）的结构，此类化合物拥有与已知细菌源活性物质迥异的全新化学骨架。通过全基因组草图测序、诱变育种以及在基因组最小化模式放线菌天蓝色链霉菌（Streptomyces coelicolor）中开展的异源生物合成实验，我们成功解析了长度为57.6 kb的氯杂菌素基因簇，该基因簇包含两个编码罕见细菌钒依赖型卤代过氧化物酶（vanadium-dependent haloperoxidase, VHPO）的基因。对两个仅在是否包含VHPO基因mcl40这一点上存在显著差异的不同黏粒（fosmid）克隆进行途径表达后，观察到氯杂菌素C的生物合成情况出现显著差异，这表明Mcl40催化了一种前所未有的、由15元环氯鎓离子诱导的大环化反应，将氯杂菌素D转化为氯杂菌素C。