Overproduction of endusamycin in Streptomyces endus subsp. aureus

Endusamycin, a naturally occurring polyether ionophore antibiotic, exhibits extensive antitumor activities. Despite its promising potential, the titer of endusamycin is significantly lower compared to widely used polyether compounds, and no reports have been published regarding its overproduction. In this study, various metabolic engineering strategies were performed to enhance endusamycin production. Notably, the deletion of competing biosynthetic gene clusters (BGCs) responsible for the biosynthesis of spore pigment and meilingmycin-like compounds based on transcriptome analysis, as well as the doubling of the endusamycin BGC, proved to be effective. These interventions resulted in a 20 % and 69 % increase in the titer of endusamycin, respectively. Furthermore, systematic optimization of fermentation medium components, including carbon source, nitrogen source, phosphorus and potassium, contributed to a further 69 % increase in the titer of endusamycin. Ultimately, the high-yielding strain YC1109 was developed through the integration of these strategies. The titer of endusamycin reached 5469 mg/L in shake-flask fermentation and 5011 mg/L in fed-batch fermentation, representing a 246 % increase compared to the original strain. This research significantly facilitates the drug development and industrialization of endusamycin. It establishes a superior chassis strain for exploring endusamycin derivatives and provides valuable insights into improving the production of polyether compounds.