Genomics-guided discovery of thailanstatins A, B, and C as pre-mRNA splicing inhibitors and antiproliferative agents from Burkholderia thailandensis MSMB43

Xiangyang Liu, Sreya Biswas, Michael G. Berg, Christopher M. Antapli, Feng Xie, Qi Wang, Man Cheng Tang, Gong Li Tang, Lixin Zhang, Gideon Dreyfuss, Yi Qiang Cheng

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Mining the genome sequence of Burkholderia thailandensis MSMB43 revealed a cryptic biosynthetic gene cluster resembling that of FR901464 (4), a prototype spliceosome inhibitor produced by Pseudomonas sp. No. 2663. Transcriptional analysis revealed a cultivation condition in which a regulatory gene of the cryptic gene cluster is adequately expressed. Consequently, three new compounds, named thailanstatins A (1), B (2), and C (3), were isolated from the fermentation broth of B. thailandensis MSMB43. Thailanstatins are proposed to be biosynthesized by a hybrid polyketide synthase-nonribosomal peptide synthetase pathway. They differ from 4 by lacking an unstable hydroxyl group and by having an extra carboxyl moiety; those differences endow thailanstatins with a significantly greater stability than 4 as tested in phosphate buffer at pH 7.4. In vitro assays showed that thailanstatins inhibit pre-mRNA splicing as potently as 4, with half-maximal inhibitory concentrations in the single to sub-μM range. Cell culture assays indicated that thailanstatins also possess potent antiproliferative activities in representative human cancer cell lines, with half-maximal growth inhibitory concentrations in the single nM range. This work provides new chemical entities for research and development and new structure-activity information for chemical optimization of related spliceosome inhibitors.

Original languageEnglish
Pages (from-to)685-693
Number of pages9
JournalJournal of Natural Products
Volume76
Issue number4
DOIs
StatePublished - 26 Apr 2013

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