Recent advances in genome-based polyketide discovery

Helfrich, Eric J. N.; Reiter, Silke; Piel, Jörn

doi:10.1016/j.copbio.2014.03.004

Cited by 90 publications

(56 citation statements)

References 53 publications

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“…Within the realm of nature, DNA‐encoding fragments of compounds are exchanged between organisms and incorporated in new structures, which can sometimes be found in different kingdoms 127. The natural product fragments are exchanged within organisms by horizontal gene or fragment gene transfer.…”

Section: Additional Sources Of Natural Product Fragment Lead Structuresmentioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody–drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products.

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Section: Additional Sources Of Natural Product Fragment Lead Structuresmentioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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“…The great benefit of the genomic era is that it enables researchers to avoid known metabolites and focus on the discovery of novel compounds based on the composition of the biosynthetic genes. Unfortunately it has also become somberingly clear that the initial bioinformatic identification of these pathways is a long way away from the eventual isolation and structure elucidation of the associated natural products (Craney et al, 2013;Helfrich et al, 2014;Kersten et al, 2011;Scherlach and Hertweck, 2009;Zerikly and Challis, 2009). Problems arise because typically only a subset of these gene clusters is expressed under standard laboratory conditions and each individual pathway may require a specific environmental signal for activation .…”

Section: Introductionmentioning

confidence: 99%

Targeted activation of silent natural product biosynthesis pathways by reporter-guided mutant selection

Guo

Xiang

et al. 2015

Metabolic Engineering

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“…However, this potential can often not be unfolded and detected under standard laboratory conditions (3,4), and, today, one challenge in the discovery of natural products is to elicit these silent/cryptic biosynthetic gene clusters. The one strain-many compounds method, where strains are cultivated under a range of growth conditions, has been suggested as a solution (5).…”

mentioning

confidence: 99%

Influence of Niche-Specific Nutrients on Secondary Metabolism in Vibrionaceae

Giubergia

Phippen

Gotfredsen

et al. 2016

Appl Environ Microbiol

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Many factors, such as the substrate and the growth phase, influence biosynthesis of secondary metabolites in microorganisms. Therefore, it is crucial to consider these factors when establishing a bioprospecting strategy. Mimicking the conditions of the natural environment has been suggested as a means of inducing or influencing microbial secondary metabolite production. The purpose of the present study was to determine how the bioactivity of Vibrionaceae was influenced by carbon sources typical of their natural environment. We determined how mannose and chitin, compared to glucose, influenced the antibacterial activity of a collection of Vibrionaceae strains isolated because of their ability to produce antibacterial compounds but that in subsequent screenings seemed to have lost this ability. The numbers of bioactive isolates were 2-and 3.5-fold higher when strains were grown on mannose and chitin, respectively, than on glucose. As secondary metabolites are typically produced during late growth, potential producers were also allowed 1 to 2 days of growth before exposure to the pathogen. This strategy led to a 3-fold increase in the number of bioactive strains on glucose and an 8-fold increase on both chitin and mannose. We selected two bioactive strains belonging to species for which antibacterial activity had not previously been identified. Using ultrahigh-performance liquid chromatography-high-resolution mass spectrometry and bioassay-guided fractionation, we found that the siderophore fluvibactin was responsible for the antibacterial activity of Vibrio furnissii and Vibrio fluvialis. These results suggest a role of chitin in the regulation of secondary metabolism in vibrios and demonstrate that considering bacterial ecophysiology during development of screening strategies will facilitate bioprospecting. IMPORTANCEA challenge in microbial natural product discovery is the elicitation of the biosynthetic gene clusters that are silent when microorganisms are grown under standard laboratory conditions. We hypothesized that, since the clusters are not lost during proliferation in the natural niche of the microorganisms, they must, under such conditions, be functional. Here, we demonstrate that an ecology-based approach in which the producer organism is allowed a temporal advantage and where growth conditions are mimicking the natural niche remarkably increases the number of Vibrionaceae strains producing antibacterial compounds.

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Recent advances in genome-based polyketide discovery

Cited by 90 publications

References 53 publications

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

Targeted activation of silent natural product biosynthesis pathways by reporter-guided mutant selection

Influence of Niche-Specific Nutrients on Secondary Metabolism in Vibrionaceae

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