Microbe Engineering to Provide Drimane-Type Building Blocks for Chiral Pool Synthesis of Meroterpenoids

Drimane-type merosesquiterpenoids (DMT) are a class of natural products with diverse structures and broad biological activity. Classical DMT synthesis relies on atom-inefficient plant-derived chiral pool building blocks, while alternative drimane-type building blocks such as drimenol and albicanol offer more direct routes but face production challenges. In this study, we engineered a microbial platform for efficient production of these building blocks. By optimizing the PhoN-IPK system through rational engineering and incorporating a Nudix hydrolase, we achieved a drimenol production of 398 mg/L and high albicanol titers of 1805 mg/L in shake flasks and 3.5 g/L in a bioreactor. Structural analysis and molecular dynamics simulations of the engineered PhoN provided insights into its improved catalytic efficiency. We demonstrated the utility of this platform by synthesizing several DMT using albicanol as the starting material, reducing the number of synthetic steps and improving overall efficiency as compared to classical approaches.