From waste to health-supporting molecules: biosynthesis of natural products from lignin-, plastic- and seaweed-based monomers using metabolically engineered Streptomyces lividans

Abstract

Background Transforming waste and nonfood materials into bulk biofuels and chemicals represents a major stride in creating a sustainable bioindustry to optimize the use of resources while reducing environmental footprint. However, despite these advancements, the production of high-value natural products often continues to depend on the use of frst-generation substrates, underscoring the intricate processes and specifc requirements of their bio‑ syntheses. This is also true for Streptomyces lividans, a renowned host organism celebrated for its capacity to produce a wide array of natural products, which is attributed to its genetic versatility and potent secondary metabolic activ‑ ity. Given this context, it becomes imperative to assess and optimize this microorganism for the synthesis of natural products specifcally from waste and nonfood substrates. Results We metabolically engineered S. lividans to heterologously produce the ribosomally synthesized and post‑ translationally modifed peptide bottromycin, as well as the polyketide pamamycin. The modifed strains success‑ fully produced these compounds using waste and nonfood model substrates such as protocatechuate (derived from lignin), 4-hydroxybenzoate (sourced from plastic waste), and mannitol (from seaweed). Comprehensive tran‑ scriptomic and metabolomic analyses ofered insights into how these substrates infuenced the cellular metabolism of S. lividans. In terms of production efciency, S. lividans showed remarkable tolerance, especially in a fed-batch process using a mineral medium containing the toxic aromatic 4-hydroxybenzoate, which led to enhanced and highly selective bottromycin production. Additionally, the strain generated a unique spectrum of pamamycins when cul‑ tured in mannitol-rich seaweed extract with no additional nutrients. Conclusion Our study showcases the successful production of high-value natural products based on the use of var‑ ied waste and nonfood raw materials, circumventing the reliance on costly, food-competing resources. S. lividans exhibited remarkable adaptability and resilience when grown on these diverse substrates. When cultured on aromatic compounds, it displayed a distinct array of intracellular CoA esters, presenting promising avenues for polyketide pro‑ duction. Future research could be focused on enhancing S. lividans substrate utilization pathways to process the intri‑ cate mixtures commonly found in waste and nonfood sources more efciently.