Gene Tweaking Boosts Spliceostatin Synthesis

Pfizer scientists have reprogrammed an engineered microbe to improve the fermentation yield of the promising cancer drug thailanstatin A, a crucial step in its further development as a chemotherapy agent (Metab. Eng. 2015, DOI: 10.1016/j.ymben.2015.11.003). Thailanstatin A is a member of the spliceostatin family of bacterial natural products that interact with the spliceosome, the protein-RNA hybrid complex that is responsible for editing mRNA before the ribosome uses it to make proteins. Misregulation of mRNA splicing and mutations in the splicing machinery are associated with several cancers, and spliceostatins can put a halt to the problems. Alessandra S. Eustáquio and colleagues previously developed a biosynthetic pathway to make more potent and stable spliceostatins, but it was limited to producing 60 mg/L of thailanstatin A. The team found a bottleneck in the pathway, which they alleviated by increasing the expression of a gene to improve selective formation of a key hydroxyl group. The reprogramming helped increase production to 2.5 g/L, a level sufficient to support clinical trials.