Engineering of new-to-nature ribosomally synthesized and post-translationally modified peptide natural products

Natural products have historically been important lead sources for drug development, particularly to combat infectious diseases. Increasingly, their structurally complex scaffolds are also envisioned as leads for applications for which they did not evolve, an approach aided by engineering of new-to-nature analogs. Ribosomally synthesized and post-translationally modified peptides (RiPPs) are promising candidates for bioengineering because they are genetically encoded and their biosynthetic enzymes display significant substrate tolerance. This review highlights recent advances in the discovery of highly unusual new reactions by genome mining and the application of engineering approaches to generate and screen novel RiPP variants. Furthermore, through the use of synthetic biology approaches, hybrid molecules with enhanced or completely new activities have been identified, which opens the door for future advancement of RiPPs as potential next-generation therapeutics.