Chemical Perturbation of Secondary Metabolism Demonstrates Important Links to Primary Metabolism

Craney, Arryn; Ozimok, Cory; Pimentel‐Elardo, Sheila Marie; Capretta, Alfredo; Nodwell, Justin R.

doi:10.1016/j.chembiol.2012.06.013

Cited by 151 publications

(139 citation statements)

References 29 publications

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“…malR is a so-called orphan luxR, a transcriptional regulator that is not adjacent to its cognate luxI homoserine lactone synthase (34), and may therefore bind alternate small molecule elicitors, such as 6 or 7. In an alternative model, stressinduced mechanisms as a result of antibiosis may be responsible for activation of malR (9,(35)(36)(37). The fact that the synthetic antibiotics (7 and the fluoroquinolones) as well as derivatives of natural ones (6, 8, and 9) elicit production of 1 appears to be consistent with this latter model.…”

Section: Discussionsupporting

confidence: 65%

High-throughput platform for the discovery of elicitors of silent bacterial gene clusters

Seyedsayamdost

2014

Proc. Natl. Acad. Sci. U.S.A.

248

235

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Over the past decade, bacterial genome sequences have revealed an immense reservoir of biosynthetic gene clusters, sets of contiguous genes that have the potential to produce drugs or drug-like molecules. However, the majority of these gene clusters appear to be inactive for unknown reasons prompting terms such as "cryptic" or "silent" to describe them. Because natural products have been a major source of therapeutic molecules, methods that rationally activate these silent clusters would have a profound impact on drug discovery. Herein, a new strategy is outlined for awakening silent gene clusters using small molecule elicitors. In this method, a genetic reporter construct affords a facile read-out for activation of the silent cluster of interest, while high-throughput screening of small molecule libraries provides potential inducers. This approach was applied to two cryptic gene clusters in the pathogenic model Burkholderia thailandensis. The results not only demonstrate a prominent activation of these two clusters, but also reveal that the majority of elicitors are themselves antibiotics, most in common clinical use. Antibiotics, which kill B. thailandensis at high concentrations, act as inducers of secondary metabolism at low concentrations. One of these antibiotics, trimethoprim, served as a global activator of secondary metabolism by inducing at least five biosynthetic pathways. Further application of this strategy promises to uncover the regulatory networks that activate silent gene clusters while at the same time providing access to the vast array of cryptic molecules found in bacteria.natural products discovery | cryptic metabolites | malleilactone

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Section: Discussionsupporting

confidence: 65%

High-throughput platform for the discovery of elicitors of silent bacterial gene clusters

Seyedsayamdost

2014

Proc. Natl. Acad. Sci. U.S.A.

248

235

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“…The first rendition of HiTES was carried out by Nodwell and coworkers (Craney et al 2012). They used Streptomyces coelicolor based on the historical importance and fruitfulness of this strain and because it synthesizes the blue polyketide actinorhodin and the red prodiginines, the production of which can be rapidly monitored.…”

Section: Applicationsmentioning

confidence: 99%

Antibiotic dialogues: induction of silent biosynthetic gene clusters by exogenous small molecules

Okada¹,

Seyedsayamdost²

2016

FEMS Microbiology Reviews

179

150

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One sentence summary: Microbial secondary metabolites represent a significant source of potential drug leads; however, the majority of the corresponding biosynthetic genes are not expressed under normal laboratory conditions. In this review, we assess the capacity of exogenous small molecules, especially antibiotics, to activate these silent gene clusters. Editor: Aimee Shen ABSTRACTNatural products have traditionally served as a dominant source of therapeutic agents. They are produced by dedicated biosynthetic gene clusters that assemble complex, bioactive molecules from simple precursors. Recent genome sequencing efforts coupled with advances in bioinformatics indicate that the majority of biosynthetic gene clusters are not expressed under normal laboratory conditions. Termed 'silent' or 'cryptic', these gene clusters represent a treasure trove for discovery of novel small molecules, their regulatory circuits and their biosynthetic pathways. In this review, we assess the capacity of exogenous small molecules in activating silent secondary metabolite gene clusters. Several approaches that have been developed are presented, including coculture techniques, ribosome engineering, chromatin remodeling and high-throughput elicitor screens. The rationale, applications and mechanisms attendant to each are discussed. Some general conclusions can be drawn from our analysis: exogenous small molecules comprise a productive avenue for the discovery of cryptic metabolites. Specifically, growth-inhibitory molecules, in some cases clinically used antibiotics, serve as effective inducers of silent biosynthetic gene clusters, suggesting that old antibiotics may be used to find new ones. The involvement of natural antibiotics in modulating secondary metabolism at subinhibitory concentrations suggests that they represent part of the microbial vocabulary through which inter-and intraspecies interactions are mediated.

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“…The latter finding provides strong incentives to focus future work on purified compounds in order to avoid masking of low abundance molecules in complex sample mixtures. Furthermore, such systematic analyses show a great promise in high-throughput screening approaches in that they allow for both screening multiple elicitors on one strain, or, as reported by Craney et al, [64] screening one elicitor molecule against a collection of strains. The major limitation to such an approach, however, remains in the massive amount of samples generated, which all require timeconsuming subsequent analytics studies.…”

Section: Additional Approaches That Facilitate Streptomycetes Engineementioning

confidence: 99%

“…[63] More recently, a library of 30 569 small molecules was screened for their effects on actinorhodin production in S. coelicolor M145. [64] This led to the isolation of a group of four antibiotic-remodeling compounds (ARCs), of which ARC2 was found capable of eliciting secondary metabolism in related Streptomyces species as well. Following these findings, the synthetic derivative Cl-ARC was used for the stronger elicitation of BGCs encoding molecules at a low abundance in a panel of fifty Actinomycete strains.…”

Section: Additional Approaches That Facilitate Streptomycetes Engineementioning

confidence: 99%

Toward Systems Metabolic Engineering of Streptomycetes for Secondary Metabolites Production

Robertsen

Weber

Kim

et al. 2017

Biotechnology Journal

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Streptomycetes are known for their inherent ability to produce pharmaceutically relevant secondary metabolites. Discovery of medically useful, yet novel compounds has become a great challenge due to frequent rediscovery of known compounds and a consequent decline in the number of relevant clinical trials in the last decades. A paradigm shift took place when the first whole genome sequences of streptomycetes became available, from which silent or "cryptic" biosynthetic gene clusters (BGCs) were discovered. Cryptic BGCs reveal a so far untapped potential of the microorganisms for the production of novel compounds, which has spurred new efforts in understanding the complex regulation between primary and secondary metabolism. This new trend has been accompanied with development of new computational resources (genome and compound mining tools), generation of various high-quality omics data, establishment of molecular tools, and other strain engineering strategies. They all come together to enable systems metabolic engineering of streptomycetes, allowing more systematic and efficient strain development. In this review, the authors present recent progresses within systems metabolic engineering of streptomycetes for uncovering their hidden potential to produce novel compounds and for the improved production of secondary metabolites.

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Chemical Perturbation of Secondary Metabolism Demonstrates Important Links to Primary Metabolism

Cited by 151 publications

References 29 publications

High-throughput platform for the discovery of elicitors of silent bacterial gene clusters

High-throughput platform for the discovery of elicitors of silent bacterial gene clusters

Antibiotic dialogues: induction of silent biosynthetic gene clusters by exogenous small molecules

Toward Systems Metabolic Engineering of Streptomycetes for Secondary Metabolites Production

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