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Proc. Natl. Acad. Sci. USA, Oct 17 2023, 120 (42) | https://doi.org/10.1073/pnas.2304668120
Identification of the lipodepsipeptide selethramide encoded in a giant nonribosomal peptide synthetase from a Burkholderia bacterium.
Sean B Romanowski # 1, Sanghoon Lee # 2, Sylvia Kunakom # 1, Bruno S Paulo 1, Michael J J Recchia 2, Dennis Y Liu 2, Hannah Cavanagh 2, Roger G Linington 2, Alessandra S Eustáquio 1 *
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607.
2Department of Chemistry, Simon Fraser University, Burnaby, BC V5H 1S6, Canada.
#Contributed equally.
*Corresponding author: correspondence to Alessandra S Eustáquio
Abstract
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
Burkholderia 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 (
R)-3-hydroxybutyric acid moiety decorates the
N-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.
논문정보
- Research article
- 2023년 10월 (BRIC 등록일 2023-10-10)
- 국외 연구진
- 의약학 > 약학
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