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Herein, we introduce a new approach that integrates microbial and chemical synthesis to generate plitidepsin and its analogues. We screened a <jats:italic>Tistrella<\/jats:italic> strain library to identify a potent didemnin B producer, and then introduced a second copy of the didemnin biosynthetic gene cluster into its genome, resulting in a didemnin B titer of approximately 75\u2005mg\/L. Next, we developed two straightforward chemical strategies to convert didemnin B into plitidepsin, one of which involved a one\u2010step synthetic route giving over 90\u2009% overall yield. Furthermore, we synthesized 13 new didemnin derivatives and three didemnin probes, enabling research into structure\u2013activity relationships and interactions between didemnin and proteins. Our study highlights the synergistic potential of biosynthesis and chemical synthesis in overcoming the challenge of producing complex natural products sustainably and at scale.<\/jats:p>","DOI":"10.1002\/anie.202318784","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T04:44:41Z","timestamp":1706676281000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Semisynthesis Platform for the Efficient Production and Exploration of Didemnin\u2010Based Drugs"],"prefix":"10.1002","volume":"63","author":[{"given":"Haili","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Chemical Biology Shenzhen Bay Laboratory  518132 Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuyang","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology Shenzhen Bay Laboratory  518132 Shenzhen 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