Engineered strains as living factories: efficient biosynthesis and modification of natural products via synthetic biology and one-pot chemical tandem reactions

Abstract

Natural products are a crucial source for drug discovery, but their traditional development is limited by resource availability, efficiency, chemical complexity, and the difficulty of rapidly diversifying biologically active scaffolds. This review addresses the central question of how biosynthetic precision and chemical diversification can be coupled when conventional metabolic engineering alone cannot fully overcome low titers, enzyme promiscuity limits, intermediate toxicity, and scale-up heterogeneity. We examine engineered strains as microbial living factories that construct stereochemically complex cores from renewable feedstocks, and one-pot chemical tandem reactions as complementary tools for post-biosynthetic functionalization, skeletal remodeling, and rapid analog generation. The review compares natural-product classes with distinct bottlenecks, analyzes mass-transfer and oxygen-limitation challenges during industrial translation, and explains domino, multicomponent, and sequential one-pot mechanisms for a microbiology-oriented readership. Recent advances in biocompatible catalysis, chemoenzymatic cascades, artificial metalloenzymes, photobiocatalysis, flow biocatalysis, and cell-free synthetic platforms are discussed as three integration paradigms: post-fermentation modification, one-pot chemoenzymatic coupling, and open cell-free manufacturing. Finally, the review outlines a roadmap for catalyst compatibility, process scale-up, regulatory assessment, and automated design-build-test-learn workflows to promote sustainable natural-product production and lead discovery.