Designer bacterial cell factories for improved production of commercially valuable non-ribosomal peptides

Non-ribosomal peptides have gained significant attention as secondary metabolites of high commercial importance. This group houses a diverse range of bioactive compounds, ranging from biosurfactants to antimicrobial and cytotoxic agents. However, low yield of synthesis by bacteria and excessive losses during purification hinders the industrial-scale production of non-ribosomal peptides, and subsequently limits their widespread applicability. While isolation of efficient producer strains and optimization of bioprocesses have been extensively used to enhance yield, further improvement can be made by optimization of the microbial strain using the tools and techniques of metabolic engineering, synthetic biology, systems biology, and adaptive laboratory evolution. These techniques, which directly target the genome of producer strains, aim to redirect carbon and nitrogen fluxes of the metabolic network towards the desired product, bypass the feedback inhibition and repression mechanisms that limit the maximum productivity of the strain, and even extend the substrate range of the cell for synthesis of the target product. The present review takes a comprehensive look into the biosynthesis of bacterial NRPs, how the same is regulated by the cell, and dives deep into the strategies that have been undertaken for enhancing the yield of NRPs, while also providing a perspective on other potential strategies that can allow for further yield improvement. Furthermore, this review provides the reader with a holistic perspective on the design of cellular factories of NRP production, starting from general techniques performed in the laboratory to the computational techniques that help a biochemical engineer model and subsequently strategize the architectural plan.