A reinvigorated era of bacterial secondary metabolite discovery

Sidebottom, Ashley M.; Carlson, Erin E.

doi:10.1016/j.cbpa.2014.10.014

Cited by 12 publications

(3 citation statements)

References 54 publications

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“…Improvements in sequencing technologies allowed whole genome sequencing of bacteria including Streptomyces (the largest genus within the Actinobacteria) and resulted in the birth of genome mining, which uses bioinformatics analysis of biosynthetic gene clusters (BGCs) to expedite discovery of NPs. These studies revealed that approximately 70% of putative BGCs differ significantly from known BGCs, − suggesting that numerous chemically diverse NPs have yet to be found . New NPs have been discovered via genome mining. − However, large scale application has been slow to be realized .…”

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confidence: 99%

Discovery of the Tyrobetaine Natural Products and Their Biosynthetic Gene Cluster via Metabologenomics

et al. 2018

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Natural products (NPs) are a rich source of medicines, but traditional discovery methods are often unsuccessful due to high rates of rediscovery. Genetic approaches for NP discovery are promising, but progress has been slow due to the difficulty of identifying unique biosynthetic gene clusters (BGCs) and poor gene expression. We previously developed the metabologenomics method, which combines genomic and metabolomic data to discover new NPs and their BGCs. Here, we utilize metabologenomics in combination with molecular networking to discover a novel class of NPs, the tyrobetaines: nonribosomal peptides with an unusual trimethylammonium tyrosine residue. The BGC for this unusual class of compounds was identified using metabologenomics and computational structure prediction data. Heterologous expression confirmed the BGC and suggests an unusual mechanism for trimethylammonium formation. Overall, the discovery of the tyrobetaines shows the great potential of metabologenomics combined with molecular networking and computational structure prediction for identifying interesting biosynthetic reactions and novel NPs.

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confidence: 99%

Discovery of the Tyrobetaine Natural Products and Their Biosynthetic Gene Cluster via Metabologenomics

et al. 2018

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“…Since the mid-20th century, activity-based screening of cultivatable microbes, mostly Actinomycetes soil bacteria, and subsequent isolation efforts enabled the discovery of numerous bioactive secondary metabolites, including various polyketides (PKs), 3 nonribosomal peptides (NRPs), and hybrids thereof (2). Advances in DNA sequencing, molecular biology, and cultivation methods have also enabled the more recent discovery of secondary metabolites from unculturable microorganisms (3)(4)(5)(6). Both microbial natural products and semisynthetic derivatives have significantly impacted human health, serving as a major source of clinically used antibiotics, antifungals, anticancer agents, immunosuppressants, and other drugs (7).…”

Section: Context For Secondary Metabolite Discoverymentioning

confidence: 99%

Natural product discovery from the human microbiome

Wilson¹,

Zha

Balskus

2017

Journal of Biological Chemistry

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Human-associated microorganisms have the potential to biosynthesize numerous secondary metabolites that may mediate important host-microbe and microbe-microbe interactions. However, there is currently a limited understanding of microbiome-derived natural products. A variety of complementary discovery approaches have begun to illuminate this microbial "dark matter," which will in turn allow detailed mechanistic studies of the effects of these molecules on microbiome and host. Herein, we review recent efforts to uncover microbiome-derived natural products, describe the key approaches that were used to identify and characterize these metabolites, discuss potential functional roles of these molecules, and highlight challenges related to this emerging research area.

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“…After nearly a century of searching for bioactive natural products, bacteria still constitute a major target of modern drug discovery 1,2 . This is in part because most bacteria can synthesize at least a few complex specialized metabolites, among which a subset exhibit biomedically relevant activities.…”

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confidence: 99%

LoaP is a broadly conserved antiterminator protein that regulates antibiotic gene clusters in Bacillus amyloliquefaciens

et al. 2017

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A valuable resource available in the search for new natural products is the diverse microbial life that spans the planet. A large subset of these microorganisms synthesize complex specialized metabolites exhibiting biomedically important activities. A limiting step to the characterization of these compounds is an elucidation of the genetic regulatory mechanisms that oversee their production. Although proteins that control transcription initiation of specialized metabolite gene clusters have been identified, those affecting transcription elongation have not been broadly investigated. In this study, we analysed the phylogenetic distribution of the large, widespread NusG family of transcription elongation proteins and found that it includes a cohesive outgroup of paralogues (herein coined LoaP), which are often positioned adjacent or within gene clusters for specialized metabolites. We established Bacillus amyloliquefaciens LoaP as a paradigm for this protein subgroup and showed that it regulated the transcriptional readthrough of termination sites located within two different antibiotic biosynthesis operons. Both of these antibiotics have been implicated in plant-protective activities, demonstrating that LoaP controls an important regulon of specialized metabolite genes for this microorganism. These data therefore reveal transcription elongation as a point of regulatory control for specialized metabolite pathways and introduce a subgroup of NusG proteins for this purpose.

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A reinvigorated era of bacterial secondary metabolite discovery

Cited by 12 publications

References 54 publications

Discovery of the Tyrobetaine Natural Products and Their Biosynthetic Gene Cluster via Metabologenomics

Discovery of the Tyrobetaine Natural Products and Their Biosynthetic Gene Cluster via Metabologenomics

Natural product discovery from the human microbiome

LoaP is a broadly conserved antiterminator protein that regulates antibiotic gene clusters in Bacillus amyloliquefaciens

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