Recent advances in engineering ribosomes for natural product biosynthesis

The translation apparatus offers many attractive features for engineering, and leveraging its powerful sequence-defined polymerization capabilities toward high-value products, such as natural products with therapeutic properties, would be transformative. The ability to produce natural products in a sequence-defined manner, that is, simply changing the mRNA input produces a variant of a natural product without having to devise an alternative synthetic scheme or synthetic metabolic pathway, would allow robust production of currently difficult-to-produce natural products and also allow production of libraries of natural product variants that could feature exciting new properties and functions. Towards this goal, we believe engineering the ribosome and its associated translation machinery remains a great candidate effort. Already pioneering efforts, especially those by the Suga group, have shown that the translation machinery is permissive to a repertoire of new substrates such as N-modified amino acids,⁵³ D-amino acids,^27,40 and b-amino acids.³⁹ While remarkable in and of itself, it points to an even greater opportunity enabled by extensive engineering of the ribosome, especially for backbone expanded monomers. Many challenges remain in the field, but also much suggest this goal is possible. Along the way, engineering the ribosome should uncover deep insights about the evolution of molecular machines as well as enabling the synthesis of exciting new macromolecules. In summary, we believe ribosome engineering stands at the cusp of innovation as an enabling technology, and has great potential to redefine the paradigm of natural product synthesis.