Epigenome manipulation as a pathway to new natural product scaffolds and their congeners

Cichewicz, Robert H.

doi:10.1039/b920860g

Cited by 250 publications

(196 citation statements)

References 176 publications

(310 reference statements)

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“…Accordingly, more highly acetylated histones are generally more loosely packed and transcriptionally accessible (Fig. 4A) (Cichewicz 2010). Further, the DNA base cytosine can be methylated to form 5-methylcytosine.…”

Section: Mechanismmentioning

confidence: 99%

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

Okada¹,

Seyedsayamdost²

2016

FEMS Microbiology Reviews

175

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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Section: Mechanismmentioning

confidence: 99%

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

Okada¹,

Seyedsayamdost²

2016

FEMS Microbiology Reviews

175

150

View full text Add to dashboard Cite

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“…In filamentous fungi the use of mutations and drugs that affect chromatin remodelling is proving to be a powerful means of pathway discovery, enabling cryptic clusters to be identified and activated (e.g. Bok et al, 2009;Cichewicz, 2010). Noncoding RNAs have also been implicated in the recruitment of chromatin complexes, and in animals Hox gene expression can be controlled posttranscriptionally and probably also epigenetically by noncoding RNAs and Polycomb group proteins (Yekta et al, 2008).…”

Section: What Is the Significance Of Clustering?mentioning

confidence: 99%

Gene Clusters for Secondary Metabolic Pathways: An Emerging Theme in Plant Biology

Osbourn

2010

Plant Physiology

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“…13 Compound 3 was obtained as a white solid. Its molecular formula was established as C 11 3.77 (3H, s, H-10)). The 13 C NMR spectrum revealed 11 carbon signals, due to one ester carbonyl, three aromatic methine carbons, three aromatic quaternary carbons, one oxygenated methine carbon, one methylene carbon, and two methyl carbons.…”

Section: Resultsmentioning

confidence: 99%

Induced biosyntheses of a novel butyrophenone and two aromatic polyketides in the plant pathogen Stagonospora nodorum

Yang

Awakawa

Wakimoto

et al. 2013

Nat. Prod. Bioprospect.

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Fungal aromatic compounds comprise an important and structurally diverse group of secondary metabolites. Several genome sequencing projects revealed many putative biosynthetic gene clusters of fungal aromatic compounds, but many of these genes seem to be silent under typical laboratory culture conditions. To gain access to this untapped reservoir of natural products, we utilized chemical epigenetic modifiers to induce the expression of dormant biosynthetic genes. As a result, the concomitant supplementation of the histone deacetylase inhibitors suberoylanilide hydroxamic acid (500 M) and nicotinamide (50 M) to the culture medium of a fungal pathogen, Stagonospora nodorum, resulted in the isolation of three aromatic compounds (1-3), including a novel natural butyrophenone, (+)-4'-methoxy-(2S)-methylbutyrophenone (1), and two known polyketides, alternariol (2) and (-)-(3R)-mellein methyl ether (3).

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Epigenome manipulation as a pathway to new natural product scaffolds and their congeners

Cited by 250 publications

References 176 publications

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

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

Gene Clusters for Secondary Metabolic Pathways: An Emerging Theme in Plant Biology

Induced biosyntheses of a novel butyrophenone and two aromatic polyketides in the plant pathogen Stagonospora nodorum

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