链霉菌基因组有很多,编码类药物化合物的生物合成基因簇(BGC)。虽然这些BGC中的一些容易产生预期的产物,许多人不这样做。生物合成隐蔽性代表了药物发现的重大障碍,支撑它的生物学机制仍然知之甚少。多环四甲酸大环内酯(PTM)抗生素的生产在链霉菌属中普遍存在,活性和隐性PTMBGC的实例是已知的。为了进一步揭示生物合成隐蔽性的原因,我们采用了以PTM为目标的比较代谢基因组学方法,分析了一组既包括不良PTM生产者又包括稳健PTM生产者的灰色链球菌进化枝菌株.通过比较这些菌株的基因组和PTM生产谱,我们系统地绘制了群内的PTM启动子结构,揭示了这些启动子是通过全球调节剂AdpA直接激活的,并发现小的启动子插入-缺失病变(indel)将较弱的PTM生产者与较强的PTM生产者区分开。我们还揭示了健壮的PTM表达与griseorhodin色素协同生产之间的意外联系,较弱的格里沙斯进化枝PTM生产者无法生产后一种化合物。这项研究强调了启动子indel和生物合成相互作用的重要性,影响BGC输出的基因编码因素,提供机械见解,无疑将扩展到其他链霉菌BGC。我们强调比较代谢基因组学是一种强大的方法来揭示基因组特征,来自较弱的抗生素生产者。这应该被证明对于合理的发现努力是有用的,并且与目前在该领域中标准的当前工程和分子信号传导方法正交。
Streptomyces genomes harbor numerous, biosynthetic gene clusters (BGCs) encoding for drug-like compounds. While some of these BGCs readily yield expected products, many do not. Biosynthetic crypticity represents a significant hurdle to drug discovery, and the biological mechanisms that underpin it remain poorly understood. Polycyclic tetramate macrolactam (PTM) antibiotic production is widespread within the Streptomyces genus, and examples of active and cryptic PTM BGCs are known. To reveal further insights into the causes of biosynthetic crypticity, we employed a PTM-targeted comparative
metabologenomics approach to analyze a panel of S. griseus clade strains that included both poor and robust PTM producers. By comparing the genomes and PTM production profiles of these strains, we systematically mapped the PTM promoter architecture within the group, revealed that these promoters are directly activated via the global regulator AdpA, and discovered that small promoter insertion-deletion lesions (indels) differentiate weaker PTM producers from stronger ones. We also revealed an unexpected link between robust PTM expression and griseorhodin pigment coproduction, with weaker S. griseus-clade PTM producers being unable to produce the latter compound. This study highlights promoter indels and biosynthetic interactions as important, genetically encoded factors that impact BGC outputs, providing mechanistic insights that will undoubtedly extend to other Streptomyces BGCs. We highlight comparative
metabologenomics as a powerful approach to expose genomic features that differentiate strong, antibiotic producers from weaker ones. This should prove useful for rational discovery efforts and is orthogonal to current engineering and molecular signaling approaches now standard in the field.