The model strain 318 of Streptomyces xiamenensis,a moderate halophile isolated from mangrove sediment with a streamlined genome (5.96Mb),produces the anti-fibrotic compounds,xiamenmycins.The relative and absolute configurations of xiamenmycin A have been characterized through total synthesis.The biosynthetic mechanism has been elucidated,and ximA～E are responsible for xiamenmycin biosynthesis.We analysed the essential metabolic network of S.xiamenensis 318 and constructed the kinetic metabolic model to provide theoretical guidance for the improvement of production.Through the medium optimization,biosynthetic gene cluster doubling and ribosome engineering,we increased the yield of xiamenmycin to 76mg/L for further pharmaceutical investigation.Xiamenmycin can attenuate hypertrophic scars by suppressing local inflammation and effects of mechanical stress.Further pharmacokinetic information showed rapid absorption and quick elimination of xiamenmycin A in vivo,and thus xiamenmcyin is a promising anti-fibrotic drug candidate for therapeutic treatment of excessive fibrotic diseases.%海岸潮间带红树林来源的厦门链霉菌(Streptomyces xiamenensis)318菌株具有天然简化的基因组(5.96Mb).从中分离得到的苯并吡喃类化合物厦门霉素具有显著抗纤维化活性.通过全合成研究,对厦门霉素的立体构型进行了确证.同时,通过生物合成途径的解析、全局性代谢网络动力学模型的分析,为构建高效的厦门霉素生物合成体系提供理论指导.经过培养基优化、生物合成基因簇加倍和核糖体工程育种,初步保障了后续的药学研究.对厦门霉素抑制增生性瘢痕的抗纤维化活性进行了体内和体外药效学研究,结果显示厦门霉素是治疗纤维化疾病的小分子药物候选物.
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