Global screening and genetic engineering of Tistrella enable sustainable production of didemnin drugs

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.