Plants produce a wide range of secondary metabolites that provide an array of benefits for human health. Challenges of native host production systems such as excessive land use, large carbon footprints, long production times, and high production costs often make plant‐based production of these critical metabolites inefficient and unsustainable. Engineered production through microbial‐based synthetic biology offers an alternative method of producing plant compounds that addresses the limitations encountered in plant‐based production. New technological and analytical tools such as bioprospecting, machine learning, and protein modeling can be used to explore biodiversity‐based data to identify more efficient enzymatic sequences for optimizing the production of plant derivatives. Ex planta production using microbial chassis systems provides a flexible, scalable metabolic platform that can more readily integrate new metabolic processes. Potential improvements include increased production rates and enhanced bioavailability of critical compounds, expanding the frontiers of metabolite production for optimized clinical applications. Microbial‐based synthetic biology also opens an avenue for sustainable production, with the capability of modifying the microbial chassis to accommodate a wide variety of substrates for feedstock. It includes the utilization of waste from human activities as carbon sources for production, presenting an opportunity to use cheap renewable resources for greener production methods. The benefits of ex planta production systems can potentially enable the efficient, scalable, and sustainable production of plant derivatives that may vastly improve health and help bring forward the realization of the 2030 UN Sustainable Development Goals.

The isoflavonoid derivatives, pterocarpans and coumestans, are explored for multiple clinical applications as osteo-regenerative, neuroprotective and anti-cancer agents. The use of plant-based systems to produce isoflavonoid derivatives is limited due to cost, scalability, and sustainability constraints. Microbial cell factories overcome these limitations in which model organisms such as Saccharomyces cerevisiae offer an efficient platform to produce isoflavonoids. Bioprospecting microbes and enzymes can provide an array of tools to enhance the production of these molecules. Other microbes that naturally produce isoflavonoids present a novel alternative as production chassis and as a source of novel enzymes. Enzyme bioprospecting allows the complete identification of the pterocarpans and coumestans biosynthetic pathway, and the selection of the best enzymes based on activity and docking parameters. These enzymes consolidate an improved biosynthetic pathway for microbial-based production systems. In this review, we report the state-of-the-art for the production of key pterocarpans and coumestans, describing the enzymes already identified and the current gaps. We report available databases and tools for microbial bioprospecting to select the best production chassis. We propose the use of a holistic and multidisciplinary bioprospecting approach as the first step to identify the biosynthetic gaps, select the best microbial chassis, and increase productivity. We propose the use of microalgal species as microbial cell factories to produce pterocarpans and coumestans. The application of bioprospecting tools provides an exciting field to produce plant compounds such as isoflavonoid derivatives, efficiently and sustainably.