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. To address this issue, Assoc. Prof. Fuzhuo Li’s laboratory collaborated with Prof. Liaobin Dong’s team at China Pharmaceutical University to develop a microbial platform for efficient production of these building blocks. By optimizing the PhoN-IPK system through rational engineering and incorporating a Nudix hydrolase, they 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. They demonstrated the utility of this platform by synthesizing several DMT including mycoleptodiscin A and pelorol, directly from albicanol. This approach significantly reduced the number of synthetic steps and improved overall efficiency compared to traditional methods, underscoring its potential for advancing natural product synthesis.

https://onlinelibrary.wiley.com/doi/10.1002/anie.202419463