Production of novel pladienolide analogues through native expression of a pathway-specific activator

Thomas J. Booth, John A. Kalaitzis, Daniel Vuong, Andrew Crombie, Ernest Lacey*, Andrew M. Piggott, Barrie Wilkinson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Aberrant splicing of pre-mRNA is implicated in many human genetic disorders. Small molecules that target the spliceosome are important leads as therapeutics and research tools, and one compound of significant interest is the polyketide natural product pladienolide B. Here, we describe the reactivation of quiescent pladienolide B production in the domesticated lab strain Streptomyces platensis AS6200 by overexpression of the pathway-specific activator PldR. The resulting dysregulation of the biosynthetic genes led to the accumulation and isolation of five additional intermediate or shunt metabolites of pladienolide B biosynthesis, including three previously unreported congeners. These compounds likely comprise the entire pladienolide biosynthetic pathway and demonstrate the link between polyketide tailoring reactions and bioactivity, particularly the importance of the 18,19-epoxide. Each congener demonstrated specific inhibitory activity against mammalian cell lines, with successive modifications leading to increased activity (IC50: 8 mM to 5 μM).

Original languageEnglish
Pages (from-to)8249-8255
Number of pages7
JournalChemical Science
Volume11
Issue number31
DOIs
Publication statusPublished - 21 Aug 2020

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