Beyond nature: in vivo production of natural product analogues through programmed biosynthetic pathways

Natural products are vital sources of medicines, and their analogues hold great promise as novel therapeutics to combat disease more effectively, including circumventing antibiotic resistance. Engineering biosynthetic pathways in microbial hosts enables efficient, cost-effective production of non-natural analogues – compounds structurally related to natural products but not necessarily derived through direct chemical modification. In this review, we highlight recent work on the in vivo production of novel natural product analogues, with an emphasis on combinatorial and precursor-directed biosynthesis, enzyme engineering, and retrobiosynthesis. We anticipate that further developments in artificial intelligence, particularly the use of machine learning models to understand enzymatic transformations and predict novel reactions, will significantly accelerate this field and drive forward its importance in drug discovery and related research.