There is a continuous need for novel microbial natural products to fill the drying-up drug development pipeline. Herein, we report myxadazoles from Myxococcus sp. SDU36, a family of novel chimeric small molecules that consist of N-ribityl 5,6-dimethylbenzimidazole and a linear fatty acid chain endowed with an isoxazole ring. The experiments of genome sequencing, gene insertion mutation, isotope labelling, and precursor feeding demonstrated that the fatty acid chain was encoded by a non-canonical PKS/NRPS gene cluster, whereas the origin of N-ribityl 5,6-dimethylbenzimidazole was related to the vitamin B₁₂ metabolism. The convergence of these two distinct biosynthetic pathways through a C-N coupling led to the unique chemical framework of myxadazoles, which is an unprecedented hybridization mode in the paradigm of natural products. Myxadazoles exhibited potent vasculogenesis promotion effect and moderate antithrombotic activity, underscoring their potential usage for the treatment of cardiovascular diseases.

中文翻译：

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粘菌唑、粘杆菌衍生的异恶唑-苯并咪唑杂种具有心血管活性

不断需要新型微生物天然产物来填补干涸的药物开发管道。在此，我们报告了来自粘球菌属的粘菌唑。SDU36，一类新型嵌合小分子，由 N-ribityl 5,6-二甲基苯并咪唑和带有异恶唑环的线性脂肪酸链组成。基因组测序、基因插入突变、同位素标记和前体补给实验表明，脂肪酸链由非规范 PKS/NRPS 基因簇编码，而 N-ribityl 5,6-二甲基苯并咪唑的起源与维生素 B ₁₂代谢。这两种不同的生物合成途径通过 CN 偶联的融合导致了粘菌唑的独特化学框架，这是天然产物范式中前所未有的杂交模式。Myxadazoles 表现出有效的血管生成促进作用和适度的抗血栓形成活性，强调了它们在治疗心血管疾病方面的潜在用途。