ABSTRACT
The Tistrella genus can produce the cyclic depsipeptide didemnin B, but the biosynthetic origin of its analogue, plitidepsin, remains unknown. Plitidepsin is an approved anticancer drug and an anti-COVID-19 agent in phase III clinical trials. Here, we employed a novel approach that combined microbial and chemical synthesis to produce plitidepsin. We first investigated the global distribution of Tistrella, which inspired us to retrieve and screen a library of Tistrella. Using a genetic approach and heterologous expression, we, for the first time, experimentally confirmed the biosynthetic gene cluster (BGC) for didemnins. After duplication of the BGC, we obtained a yield of didemnin B reached to 70 mg/L in the engineered strain. We then developed two chemical strategies to convert didemnin B to plitidepsin, one of which resulted in over 90% overall yield in a one-step synthetic route. Additionally, we synthesized two new didemnin analogues and assessed their anticancer and antiviral activities. Our study provides a practical and sustainable solution for producing plitidepsin and its derivatives, which may expedite didemnin drug development.