Combining active-site mutability landscapes and pathway engineering in Bacillus subtilis to boost amorphadiene and taxadiene biosynthesis
Medicines like artemisinin (an antimalarial drug) and paclitaxel (a cancer therapy) begin as complex plant terpenoids. Traditionally, these compounds are extracted from slow growing plants or made by costly, multi step chemistry. In this thesis, we show how a common soil microbe, Bacillus subtilis, can be reprogrammed into a mini “factory” to produce these valuable molecules faster, cheaper, and more sustainably.
By installing powerful genetic tools, rewiring central metabolism, and redesigning the key enzymes that assemble terpenoids, we achieved record yields of the immediate precursors to artemisinin and paclitaxel. Along the way, we mapped how tiny changes in enzyme structure flip their product profiles—knowledge that will guide future drug manufacture.
This work not only paves the way for microbial production of lifesaving medications but also provides a blueprint for using biology to make complex natural products with minimal environmental impact.