Streptomyces has the largest repertoire of natural product biosynthetic gene clusters (BGCs), yet developing a universal engineering strategy for each Streptomyces species is challenging. Given that some Streptomyces species have larger BGC repertoires than others, we proposed that a set of genes co-evolved with BGCs to support biosynthetic proficiency must exist in those strains, and that their identification may provide universal strategies to improve the productivity of other strains. We show here that genes co-evolved with natural product BGCs in Streptomyces can be identified by phylogenomics analysis. Among the 597 genes that co-evolved with polyketide BGCs, 11 genes in the ‘coenzyme’ category have been examined, including a gene cluster encoding for the cofactor pyrroloquinoline quinone. When the pqq gene cluster was engineered into 11 Streptomyces strains, it enhanced production of 16,385 metabolites, including 36 known natural products with up to 40-fold improvement and several activated silent gene clusters. This study provides an innovative engineering strategy for improving polyketide production and finding previously unidentified BGCs.

链霉菌拥有最大的天然产物生物合成基因簇 (BGC)，但为每种链霉菌开发通用的工程策略具有挑战性。鉴于某些链霉菌物种比其他物种具有更大的 BGC 库，我们提出这些菌株中必须存在一组与 BGC 共同进化以支持生物合成能力的基因，并且它们的识别可能提供提高其他菌株生产力的通用策略。我们在此表明​​，可以通过系统基因组学分析来鉴定与链霉菌中天然产物 BGC 共同进化的基因。在与聚酮化合物 BGC 共同进化的 597 个基因中，已检查了“辅酶”类别中的 11 个基因，其中包括编码辅因子吡咯并喹啉醌的基因簇。当pqq基因簇被工程化到 11 个链霉菌菌株中时，它增强了 16,385 种代谢物的产生，其中包括 36 种已知的天然产物，产量提高了 40 倍，以及几个激活的沉默基因簇。这项研究提供了一种创新的工程策略，用于提高聚酮化合物的生产并发现以前未识别的 BGC。