Valhidepsin Lipopeptides from Chromobacterium vaccinii: Structures, Biosynthesis, and Coregulation with FR900359 Production
- Dominik Pistorius*Dominik Pistorius*Phone: +41 792299811. Email: [email protected]Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, 4056 Basel, SwitzerlandMore by Dominik Pistorius
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- Kathrin BuntinKathrin BuntinGlobal Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, 4056 Basel, SwitzerlandMore by Kathrin Buntin
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- Etienne RichardEtienne RichardGlobal Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, 4056 Basel, SwitzerlandMore by Etienne Richard
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- Michael RustMichael RustGlobal Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, 4056 Basel, SwitzerlandMore by Michael Rust
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- Caroline BouquetCaroline BouquetGlobal Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, 4056 Basel, SwitzerlandMore by Caroline Bouquet
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- Séverine WollbrettSéverine WollbrettGlobal Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, 4056 Basel, SwitzerlandMore by Séverine Wollbrett
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- Eric WeberEric WeberGlobal Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, 4056 Basel, SwitzerlandMore by Eric Weber
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- Daniele DietschinDaniele DietschinGlobal Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, 4056 Basel, SwitzerlandMore by Daniele Dietschin
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- Robert BruccoleriRobert BruccoleriCongenomics, LLC, Glastonbury, Connecticut 06033, United StatesMore by Robert Bruccoleri
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- Edward OakeleyEdward OakeleyChemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, 4056 Basel, SwitzerlandMore by Edward Oakeley
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- Frank PetersenFrank PetersenGlobal Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, 4056 Basel, SwitzerlandMore by Frank Petersen
Abstract
Microbial secondary metabolites continue to provide a valuable source of both chemical matter and inspiration for drug discovery in a broad range of therapeutic areas. Beyond this, the corresponding microorganisms represent a sustainable modality for biotechnological production of structurally complex molecules at the quantities required for drug development or even commercial manufacturing. Chromobacterium vaccinii, which has recently been reported as a producer of the pharmacologically highly important Gq inhibitor FR900359 (FR), represents such an example. The characterization of an orphan biosynthetic gene cluster (BGC) located directly downstream of the frs BCG led to the discovery of eight new lipopeptides, valhidepsins A–H (1–8), produced by C. vaccinii. Their chemical structures were elucidated through analysis of 1D and 2D NMR data and high-resolution MS/MS fragmentation methods. The valhidepsins did not display significant antibiotic nor cytotoxic activities but showed surfactant properties. The cluster–compound correlation was demonstrated by generation of a knockout mutant, which abolished production of valhidepsins. This knockout mutant yielded a significantly increased isolated yield of FR.
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