The Role of Combinatorial Biosynthesis in Natural Products Discovery

Natural products possess unrivaled chemical and structural diversity and, correspondingly, a wide range of biological activities. Combinatorial biosynthesis is traditionally defined as the generation of natural product analogues through the use of genetic engineering of biosynthetic pathways. Platensimycin (PTM) and platencin (PTN) are a new class of promising antibiotic and antidiabetic drug leads. They are effective against a wide range of gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Mycobacterium tuberculosis. Complementary to chemical synthesis, combinatorial biosynthesis provides an alternative to generating natural product structural diversity. Natural product discovery has had a profound impact on modern human health and has inspired both biology and drug therapy. Discovery-based combinatorial biosynthesis can supplement the knowledge-based approach by discovering novel natural products, biosynthetic gene clusters, and enzyme functions. The power of combinatorial biosynthesis by discovery is the ability to probe Nature for a desired structural motif while allowing the rest of the natural product scaffold to change.