Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
Cell Chem Biol. 2021 Apr 15;28(4):515-523.e5. doi: 10.1016/j.chembiol.2020.12.011. Epub 2021 Jan 12.
The formicamycins are promising antibiotics first identified in Streptomyces formicae KY5, which produces the compounds at low levels. Here, we show that by understanding the regulation of the for biosynthetic gene cluster (BGC), we can rewire the BGC to increase production levels. The for BGC consists of 24 genes expressed on nine transcripts. The MarR regulator ForJ represses expression of seven transcripts encoding the major biosynthetic genes as well as the ForGF two-component system that initiates biosynthesis. We show that overexpression of forGF in a ΔforJ background increases formicamycin production 10-fold compared with the wild-type. De-repression, by deleting forJ, also switches on biosynthesis in liquid culture and induces the production of additional, previously unreported formicamycin congeners. Furthermore, combining de-repression with mutations in biosynthetic genes leads to biosynthesis of additional bioactive precursors.
甲酸霉素是一类有前景的抗生素，最初是在链霉菌属（Streptomyces formicae）KY5 中发现的，该菌株以低水平的方式产生这些化合物。在这里，我们表明，通过了解生物合成基因簇（BGC）的调控，我们可以重新布线 BGC 以提高生产水平。该 BGC 由 24 个基因组成，在九个转录本上表达。MarR 调节剂 ForJ 抑制表达七种转录本，这些转录本编码主要生物合成基因以及启动生物合成的 ForGF 双组分系统。我们表明，在 ΔforJ 背景下过表达 forGF 与野生型相比，使甲酸霉素的产量增加了 10 倍。通过删除 forJ 进行去阻遏，也能在液体培养中打开生物合成，并诱导产生以前未报道过的其他甲酸霉素同系物。此外，将去阻遏与生物合成基因的突变相结合，导致产生其他生物活性前体的生物合成。
