Identification of the lipodepsipeptide selethramide encoded in a giant nonribosomal peptide synthetase from a Burkholderia bacterium

Bacterial natural products have found many important industrial applications. Yet traditional discovery pipelines often prioritize individual natural product families despite the presence of multiple natural product biosynthetic gene clusters in each bacterial genome. Systematic characterization of...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2023-10, Vol.120 (42), p.e2304668120
Main Authors: Romanowski, Sean B, Lee, Sanghoon, Kunakom, Sylvia, Paulo, Bruno S, Recchia, Michael J J, Liu, Dennis Y, Cavanagh, Hannah, Linington, Roger G, Eustáquio, Alessandra S
Format: Article
Language:English
Subjects:
Bacteria
Biological Products - chemistry
Biological Sciences
Biosynthesis
Burkholderia
Burkholderia - genetics
Chromosome 1
Chromosomes
Data acquisition
Deletion mutant
Deoxyribonucleic acid
DNA
DNA methylation
Fungicides
Gene clusters
Genomes
Humans
Industrial applications
Leucine
Lipopeptides - chemistry
Metabolomics
Mimicry
Motility
Multigene Family
Mutants
Natural products
Peptide Synthases - genetics
Peptides
Plasmids
Serine
Serine - genetics
Swarming
Threonine
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Summary:Bacterial natural products have found many important industrial applications. Yet traditional discovery pipelines often prioritize individual natural product families despite the presence of multiple natural product biosynthetic gene clusters in each bacterial genome. Systematic characterization of talented strains is a means to expand the known natural product space. Here, we report genomics, epigenomics, and metabolomics studies of sp. FERM BP-3421, a soil isolate and known producer of antitumor spliceostatins. Its genome is composed of two chromosomes and two plasmids encoding at least 29 natural product families. Metabolomics studies showed that FERM BP-3421 also produces antifungal aminopyrrolnitrin and approved anticancer romidepsin. From the orphan metabolome features, we connected a lipopeptide of 1,928 Da to an 18-module nonribosomal peptide synthetase encoded as a single gene in chromosome 1. Isolation and structure elucidation led to the identification of selethramide which contains a repeating pattern of serine and leucine and is cyclized at the side chain oxygen of the one threonine residue at position 13. A ( )-3-hydroxybutyric acid moiety decorates the -terminal serine. Initial attempts to obtain deletion mutants to probe the role of selethramide failed. After acquiring epigenome (methylome) data for FERM BP-3421, we employed a mimicry by methylation strategy that improved DNA transfer efficiency. Mutants defective in selethramide biosynthesis showed reduced surfactant activity and impaired swarming motility that could be chemically complemented with selethramide. This work unveils a lipopeptide that promotes surface motility, establishes improved DNA transfer efficiency, and sets the stage for continued natural product identification from a prolific strain.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2304668120