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Engineered biosynthesis of an antibiotic meroterpenoid toward industrial production

Elucidation of ascofuranone and ascochlorin biosyntheses and their metabolic engineering

Ascofuranone (AF) and ascochlorin (AC) are fungal natural products with similar chemical structures, isolated from Acremonium egyptiacum. Both have many useful biological properties; in particular, AF is a promising drug candidate against the tropical disease, African trypanosomiasis. However, the difficulty of the synthetic method and the inaccessibility of bioengineering methods have hampered industrial production. Researchers in The University of Tokyo, Nagasaki University, Riken, and Kikkoman Corporation, have elucidated the complete biosynthetic pathways of AF/AC which branches from the common precursor into two different terpene cyclizations to produce AF and AC. With the biosynthetic knowledge in their hands, the team created the fungal strain, which selectively produces AF with higher yield (~500 mg/L) than wild type by blocking the AC biosynthetic pathway with genetic manipulation. This study leads to cost-effective fermentative production of AF. In this paper, the authors created a microorganism which produce a promising drug seed through genetic engineering. They expect that “Our results could pave the way for the development of novel antibiotic production system by bioengineering and lead to the mass production of the microbial antibiotics with efficient and easy way.”

This work is financially supported by JSPS KAKENHI (JP17H04763, JP17KT0095, JP17K15679, 23117004, JP16H06443, JP18K19139, and 26253025), Grant-in-Aid for Scientific Research on Innovative Areas “Creation of Complex Functional Molecules by Rational Redesign of Biosynthetic Machineries”, Japanese Initiative for Progress of Research on Infectious Disease for global Epidemic, JST/NSFC Strategic International Collaborative Research Program, and Research Program on Emerging and Re-emerging Infectious Diseases. We also acknowledge support from the Program for Promotion of Basic and Applied Researches for Innovations in Bio-oriented Industry (BRAIN) and from the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry.