Identification and engineering of 32 membered antifungal macrolactone notonesomycins

• Main Authors: Goh, Falicia, Zhang, Mingzi M., Lim, Tian Ru, Low, Kia Ngee, Nge, Choy Eng, Heng, Elena, Yeo, Wan Lin, Sirota, Fernanda L., Crasta, Sharon, Tan, Zann, Ng, Veronica, Leong, Chung Yan, Zhang, Huibin, Lezhava, Alexander, Chen, Swaine L., Hoon, Shawn S., Eisenhaber, Frank, Eisenhaber, Birgit, Kanagasundaram, Yoganathan, Wong, Fong T., Ng, Siew Bee
• Other Authors: School of Computer Science and Engineering
• Format: Article
• Language: English
• Published: 2021
• Subjects: Engineering::Bioengineering; Natural Product; Polyketide
• Online Access: https://hdl.handle.net/10356/147974
• Institution: Nanyang Technological University

Notonesomycin A is a 32-membered bioactive glycosylated macrolactone known to be produced by Streptomyces aminophilus subsp. notonesogenes 647-AV1 and S. aminophilus DSM 40186. In a high throughput antifungal screening campaign, we identified an alternative notonesomycin A producing strain, Streptomyces sp. A793, and its biosynthetic gene cluster. From this strain, we further characterized a new more potent antifungal non-sulfated analogue, named notonesomycin B. Through CRISPR-Cas9 engineering of the biosynthetic gene cluster, we were able to increase the production yield of notonesomycin B by up to 18-fold as well as generate a strain that exclusively produces this analogue.