Fermentation Optimization of Loonamycin Production by Marine <i>Nocardiopsis flavescens</i>

The antitumor drug candidate, loonamycin, was isolated from Nocardiopsis flavescens NA01583 and exerts its antitumor activity by inhibiting topoisomerase I activity. However, the current production levels of loonamycin are insufficient for further research. To address this limitation, a liquid fermentation method was developed, optimizing both fermentation conditions and medium components. This optimization increased loonamycin production from 1 mg/mL on agar plate to 602.32 mg/mL in shake flask and ultimately 532.51 mg/mL in a 5-L bioreactor. Exogenous addition experiments revealed that sea salt and metal ions significantly inhibit loonamycin synthesis. Multi-temporal transcriptomic analyses indicated that the reduced expression levels of genes involved in the shikimate pathway and L-tryptophan biosynthesis pathway were the limiting factors for increased loonamycin yield. Overall, an effective fermentation method for rare marine actinomycetes was established, significantly enhancing loonamycin production and providing a foundation for the development of this novel antitumor prodrug.