Peptides derived from non-ribosomal peptide synthetases (NRPSs) represent an important class of pharmaceutically relevant drugs. Methods to generate novel non-ribosomal peptides or to modify peptide natural products in an easy and predictable way are therefore of great interest. However, although the overall modular structure of NRPSs suggests the possibility of adjusting domain specificity and selectivity, only a few examples have been reported and these usually show a severe drop in production titre. Here we report a new strategy for the modification of NRPSs that uses defined exchange units (XUs) and not modules as functional units. XUs are fused at specific positions that connect the condensation and adenylation domains and respect the original specificity of the downstream module to enable the production of the desired peptides. We also present the use of internal condensation domains as an alternative to other peptide-chain-releasing domains for the production of cyclic peptides.

源自非核糖体肽合成酶（NRPS）的肽代表了一类重要的药物相关药物。因此，以简单且可预测的方式产生新的非核糖体肽或修饰肽天然产物的方法引起了极大的兴趣。但是，尽管NRPS的整体模块结构暗示了调节域特异性和选择性的可能性，但仅报道了少数几个例子，这些例子通常显示出生产效价的严重下降。在这里，我们报告了一种新的NRPS修改策略，该策略使用已定义的交换单元（XU）而不是模块作为功能单元。XU在连接缩合和腺苷酸化域的特定位置融合，并尊重下游模块的原始特异性，从而能够生产所需的肽。