A Synthetic, Species‐Specific Activator of Secondary Metabolism and Sporulation in <i>Streptomyces coelicolor</i>

Ahmed, Salman; Craney, Arryn; Pimentel‐Elardo, Sheila Marie; Nodwell, Justin R.

doi:10.1002/cbic.201200619

Cited by 27 publications

(27 citation statements)

References 43 publications

(28 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Heightened compound production will likely require use of other established strategies such as genetic manipulation,(46) co-culturing of S. coelicolor ,(42) and/or further variations to the growth media such as pH or addition of small molecule perturbants. (47, 48)…”

Section: Resultsmentioning

confidence: 99%

Integrated Metabolomics Approach Facilitates Discovery of an Unpredicted Natural Product Suite from Streptomyces coelicolor M145

et al. 2013

View full text Add to dashboard Cite

Natural products exhibit a broad range of biological properties and have been a crucial source of therapeutic agents and novel scaffolds. Although bacterial secondary metabolomes are widely explored, they remain incompletely cataloged by current isolation and characterization strategies. To identify metabolites residing in unexplored chemical space, we have developed an integrated discovery approach that combines bacterial growth perturbation, accurate mass spectrometry, comparative mass spectra data analysis, and fragmentation spectra clustering for the identification of low-abundant, novel compounds from complex biological matrices. In this investigation, we analyzed the secreted metabolome of the extensively studied Actinomycete, Streptomyces coelicolor M145, and discovered a low-abundant suite of 15 tri-hydroxamate, amphiphilic siderophores. Compounds in this class have primarily been observed in marine microorganisms making their detection in the soil-dwelling S. coelicolor M145 significant. At least ten of these ferrioxamine-based molecules are not known to be produced by any organism and none have previously been detected from S. coelicolor M145. In addition, we confirmed the production of ferrioxamine D1, a relatively hydrophilic family member that has not been shown to be biosynthesized by this organism. The identified molecules are part of only a small list of secondary metabolites that have been discovered since sequencing of S. coelicolor M145 revealed that it possessed numerous putative secondary metabolite-producing gene clusters with no known metabolites. Thus, the identified siderophores represent the unexplored metabolic potential of both well-studied and new organisms that could be uncovered with our sensitive and robust approach.

show abstract

Section: Resultsmentioning

confidence: 99%

Integrated Metabolomics Approach Facilitates Discovery of an Unpredicted Natural Product Suite from Streptomyces coelicolor M145

et al. 2013

View full text Add to dashboard Cite

show abstract

“…This link between fatty acid and polyketide biosynthesis, the authors proposed, helps set the upper limit on polyketide yields. Recent results show that the regulatory mechanism by ARC2 might be more complex and future studies will likely shed more light on this issue (Ahmed et al 2013).…”

Section: Mechanismmentioning

confidence: 99%

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

Okada¹,

Seyedsayamdost²

2016

FEMS Microbiology Reviews

176

150

View full text Add to dashboard Cite

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.

show abstract

“…The ARC2 series (ARC2, ARC3, ARC4, and ARC5) were structurally related to triclosan, a synthetic antibiotic (Craney et al, 2012). Particularly, ARC2 altered the secondary metabolite output in all of the tested streptomycetes (Craney et al, 2012;Ahmed et al, 2013). These probes appear to have the potential to widely use as active elicitors for mining secondary metabolite.…”

Section: Activation Of Cryptic Gene Clusters By Chemical or Physical mentioning

confidence: 99%

The Application of Regulatory Cascades in Streptomyces: Yield Enhancement and Metabolite Mining

Xia

et al. 2020

Front. Microbiol.

View full text Add to dashboard Cite

Streptomyces is taken as an important resource for producing the most abundant antibiotics and other bio-active natural products, which have been widely used in pharmaceutical and agricultural areas. Usually they are biosynthesized through secondary metabolic pathways encoded by cluster situated genes. And these gene clusters are stringently regulated by interweaved transcriptional regulatory cascades. In the past decades, great advances have been made to elucidate the regulatory mechanisms involved in antibiotic production in Streptomyces. In this review, we summarized the recent advances on the regulatory cascades of antibiotic production in Streptomyces from the following four levels: the signals triggering the biosynthesis, the global regulators, the pathway-specific regulators and the feedback regulation. The production of antibiotic can be largely enhanced by rewiring the regulatory networks, such as overexpression of positive regulators, inactivation of repressors, fine-tuning of the feedback and ribosomal engineering in Streptomyces. The enormous amount of genomic sequencing data implies that the Streptomyces has potential to produce much more antibiotics for the great diversities and wide distributions of biosynthetic gene clusters in Streptomyces genomes. Most of these gene clusters are defined cryptic for unknown or undetectable natural products. In the synthetic biology era, activation of the cryptic gene clusters has been successfully achieved by manipulation of the regulatory genes. Chemical elicitors, rewiring regulatory gene and ribosomal engineering have been employed to crack the potential of cryptic gene clusters. These have been proposed as the most promising strategy to discover new antibiotics. For the complex of regulatory network in Streptomyces, we proposed that the discovery of new antibiotics and the optimization of industrial strains would be greatly promoted by further understanding the regulatory mechanism of antibiotic production.

show abstract

A Synthetic, Species‐Specific Activator of Secondary Metabolism and Sporulation in Streptomyces coelicolor

Cited by 27 publications

References 43 publications

Integrated Metabolomics Approach Facilitates Discovery of an Unpredicted Natural Product Suite from Streptomyces coelicolor M145

Integrated Metabolomics Approach Facilitates Discovery of an Unpredicted Natural Product Suite from Streptomyces coelicolor M145

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

The Application of Regulatory Cascades in Streptomyces: Yield Enhancement and Metabolite Mining

Contact Info

Product

Resources

About