Challenges and opportunities for natural product discovery, production, and engineering in native producers versus heterologous hosts.

Recent advances and emerging technologies for metabolic pathway engineering and synthetic biology have transformed the field of natural product discovery, production, and engineering. Despite these advancements, there remain many challenges in understanding how biosynthetic gene clusters are silenced or activated, including changes in the transcription of key biosynthetic and regulatory genes. This knowledge gap is highlighted by the success and failed attempts of manipulating regulatory genes within biosynthetic gene clusters in both native producers and heterologous hosts. These complexities make the choice of native producers versus heterologous hosts, fermentation medium, and supply of precursors crucial factors in achieving the production of the target natural products and engineering designer analogs. Nature continues to serve as inspiration for filling the knowledge gaps and developing new research strategies. By exploiting the evolutionary power of nature, alternative producers, with the desired genetic amenability and higher titers of the target natural products, and new strains, harboring gene clusters that encode evolutionary optimized congeners of the targeted natural product scaffolds, can be discovered. These newly identified strains can serve as an outstanding biotechnology platform for the engineered production of sufficient quantities of the target natural products and their analogs, enabling biosynthetic studies and potential therapeutic applications. These challenges and opportunities are showcased herein using fredericamycin, iso-migrastatin, platencin and platensimycin, the enediynes of C-1027, tiancimycin, and yangpumicin, and the leinamycin family of natural products.