Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) / Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, 66123, Saarbrücken, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany.
Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) / Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, 66123, Saarbrücken, Germany.
Metab Eng. 2019 Sep;55:201-211. doi: 10.1016/j.ymben.2019.07.010. Epub 2019 Jul 21.
Corallopyronins (COR) are α-pyrone antibiotics from myxobacteria representing highly promising lead structures for the development of antibacterial therapeutic agents. Their ability to inhibit RNA polymerase through interaction with the "switch region", a novel target, distant from binding sites of previously characterized RNA polymerase inhibitors (e.g. rifampicin), makes them particularly promising as antibiotic candidates. Corallopyronin A is currently also investigated as a lead compound for the treatment of lymphatic filariasis because of its superb activity against the nematode symbiont Wolbachia. As total synthesis is not a valid production option biotechnological optimization of compound supply is of utmost importance to further develop this highly potent compound class. Here we describe decisive improvements of the previously reported heterologous COR production and engineering platform yielding production of ~100 mg/L COR A. Furthermore, we provide a revised model of COR biosynthesis shedding light on the function of several biosynthetic proteins, including an unusual ECH-like enzyme providing dehydration functionality in trans and an uncharacterized protein conferring COR self-resistance in the myxobacterial heterologous host Myxococcus xanthus DK1622. We also report two new COR derivatives, COR D and oxyCOR A discovered in genetically engineered strains.
珊瑚素（COR）是粘细菌产生的α-吡喃酮类抗生素，代表了极具发展前景的抗菌治疗药物先导结构。其通过与“开关区域”（一个新颖的靶点）相互作用抑制 RNA 聚合酶的能力，使其与先前表征的 RNA 聚合酶抑制剂（如利福平）的结合位点相去甚远，这使它们成为极具潜力的抗生素候选物。由于珊瑚素 A 对线虫共生体沃尔巴克氏体具有极好的活性，因此目前也被作为治疗淋巴丝虫病的先导化合物进行研究。由于全合成不是一种有效的生产方法，因此化合物供应的生物技术优化对于进一步开发这种高效化合物类别至关重要。在这里，我们描述了对先前报道的异源 COR 生产和工程平台的决定性改进，该平台可生产约 100mg/L 的 COR A。此外，我们提供了 COR 生物合成的修订模型，阐明了几种生物合成蛋白的功能，包括提供反式脱水功能的不寻常 ECH 样酶和在粘细菌异源宿主粘球菌 DK1622 中赋予 COR 自身抗性的未表征蛋白。我们还报告了在遗传工程菌株中发现的两种新的 COR 衍生物，即 COR D 和 oxyCOR A。
