Anthracycline biosynthesis in Streptomyces: engineering, resistance and antimicrobial activity

Hulst, M.B. (2024)

Doctoral Thesis

Actinobacteria are well known for the production of bioactive natural products, many of which have applications in the fields of human, animal and plant health. Subject of this thesis are the anthracyclines, glycosylated aromatic polyketides with potent anticancer activity. Despite remarkable efficacy against acute leukaemia and various solid tumours, their application is limited by severe side effects, such as cardiotoxicity, therapy-related tumours and infertility.
Recent insights into the mode-of-action of anthracyclines have prompted renewed interest into this important class of anticancer compounds. One of the most promising compounds is N,N-dimethyldoxorubicin, which exerts significantly reduced side effects. To date, DMdoxo has not been isolated from natural sources, but biosynthesis would be an attractive option for scaling up production of this promising compound.
For this reason, we aimed to engineer the Doxo biosynthetic pathway in S. peucetius for the production of biosynthetic N,N-dimethylated anthracyclines. The challenges that we encountered instigated the study of anthracycline resistance mechanisms in Streptomyces, and potential applications of detoxified anthracyclines as antibiotics. Finally, to facilitate future screening and strain engineering efforts of Streptomyces producer strains, we developed a workflow for integrated quantitative proteomics and metabolomics from small-scale Streptomyces cultures

• Streptomyces
• Biosynthesis
• Anthracyclines
• Anticancer
• Metabolic engineering
• Natural products

• All authors: Hulst, M.B.
• Supervisor: Wezel, G.P. van; Neefjes, J.J.C.
• Committee: Meijer, G.P.; Martin, N.I.; Hertog, J. den; Pronk, J.T.; Nybo, E.
• Qualification: Doctor (dr.)
• Awarding Institution: Institute of Biology Leiden (IBL), Faculty of Science, Leiden University
• Date: 2024-06-20