Engineering Heterologous Hosts for the Enhanced Production of Non-ribosomal Peptides

Non-ribosomal peptides (NRPs) are a family of secondary metabolites with the highest number among entire secondary metabolite types. They are biosynthesized by a multi-modular enzyme complex called non-ribosomal peptide synthetase (NRPS), which is encoded by a biosynthetic gene cluster (BGC) in plants and a special group of microorganisms. NRPs are structurally and functionally diverse with numerous industrial applications. However, native producers of these valuable NRPs have several biotechnological limitations for efficient production, including their slow growth, inefficient genetic manipulations, and silent BGCs. Heterologous expression of NRPS can address these challenges, especially using an array of model organisms with well-studied metabolic networks and readily available genetic engineering tools. Here, we review the applications of representative bacterial heterologous hosts, namely representative model Streptomyces species, Escherichia coli, Pseudomonas putida, and Bacillus subtilis, which have been engineered for the enhanced production of NRPs.