Actinomycetes biosynthetic potential: how to bridge in silico and in vivo?

Rebets, Yuriy; Brötz, Elke; Tokovenko, Bogdan; Luzhetskyy, Andriy

doi:10.1007/s10295-013-1352-9

Cited by 59 publications

(40 citation statements)

References 124 publications

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“…Genetic regulation of secondary metabolism remains poorly understood across the diversity of secondary metabolite producing organisms and identifying a low abundance discrete predicted metabolite from within a crude metabolome is a non-trivial challenge. Consequently, more recently, a host of methods for activating regulated secondary metabolism have been developed with the ability to unlock tightly regulated clusters [11, 26, 51, 61, 76]. In combination with ‘looking harder’, and given the rate limiting steps of isolation and structural elucidation, these approaches can likely occupy discovery efforts for some time.…”

Section: How Should Microbial Genomes Be Mined?mentioning

confidence: 99%

“…Evidence is increasing that a significant fraction of secondary metabolism in microorganisms can be activated to isolable levels by chemical and biochemical cues [48, 51, 61, 67, 72, 76]. A molecular understanding of the connection of these queues to specific transcriptional, translational, or other metabolic elements across genera would no doubt be very valuable in this context.…”

Section: How Can Progress On Genome Mining Be Accelerated?mentioning

confidence: 99%

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Microbial genome mining for accelerated natural products discovery: is a renaissance in the making?

Bachmann

Lanen

Baltz³

2014

Journal of Industrial Microbiology and Biotechnology

246

187

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Microbial genome mining is a rapidly developing approach to discover new and novel secondary metabolites for drug discovery. Many advances have been made in the past decade to facilitate genome mining, and these are reviewed in this Special Issue of the Journal of Industrial Microbiology and Biotechnology. In this Introductory Review, we discuss the concept of genome mining and why it is important for the revitalization of natural product discovery; what microbes show the most promise for focused genome mining; how microbial genomes can be mined; how genome mining can be leveraged with other technologies; how progress on genome mining can be accelerated; and who should fund future progress in this promising field. We direct interested readers to more focused reviews on the individual topics in this Special Issue for more detailed summaries on the current state-of-the-art.

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Section: How Should Microbial Genomes Be Mined?mentioning

confidence: 99%

Section: How Can Progress On Genome Mining Be Accelerated?mentioning

confidence: 99%

Microbial genome mining for accelerated natural products discovery: is a renaissance in the making?

Bachmann

Lanen

Baltz³

2014

Journal of Industrial Microbiology and Biotechnology

246

187

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“…Several methods have been developed to activate these silent gene clusters, such as overexpression of a pathway-specific activator, manipulation of global transcriptional regulators, mutation in the RNA polymerase subunits, ribosome engineering, uses of histone deacetylase inhibitors, cultures in different growth conditions or heterologous expression in a host engineered for expression. These methods have been described in different reviews (see in this issue [22,53,58,75] and for example [2,21,48,52,69]) and will therefore not be presented here.…”

Section: Introductionmentioning

confidence: 99%

Genome mining of Streptomyces ambofaciens

Aigle

Lautru

Spiteller

et al. 2014

Journal of Industrial Microbiology and Biotechnology

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Since the discovery of the streptomycin produced by Streptomyces griseus in the middle of the last century, members of this bacterial genus have been largely exploited for the production of secondary metabolites with wide uses in medicine and in agriculture. They have even been recognized as one of the most prolific producers of natural products among microorganisms. With the onset of the genomic era, it became evident that these microorganisms still represent a major source for the discovery of novel secondary metabolites. This was highlighted with the complete genome sequencing of Streptomyces coelicolor A3(2) which revealed an unexpected potential of this organism to synthesize natural products undetected until then by classical screening methods. Since then, analysis of sequenced genomes from numerous Streptomyces species has shown that a single species can carry more than 30 secondary metabolite gene clusters, reinforcing the idea that the biosynthetic potential of this bacterial genus is far from being fully exploited. This review highlights our knowledge on the potential of Streptomyces ambofaciens ATCC 23877 to synthesize natural products. This industrial strain was known for decades to only produce the drug spiramycin and another antibacterial compound, congocidine. Mining of its genome allowed the identification of 23 clusters potentially involved in the production of other secondary metabolites. Studies of some of these clusters resulted in the characterization of novel compounds and of previously known compounds but never characterized in this Streptomyces species. In addition, genome mining revealed that secondary metabolite gene clusters of phylogenetically closely related Streptomyces are mainly species-specific.

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“…While Actinobacteria were the sources of new antibiotics in the 1960-70s, progressively fewer and fewer new antibiotics were found since then, feeding a growing disappointment and disbelief in the ability to find more novel compounds. However, it is now recognized [5,6] that most of the BGCs (biosynthetic gene clusters) are silent and require activation to produce compounds. Thus, genome-based estimate, which also includes silent BGCs, is important for the revival of interest and belief in the potential of Actinobacteria.…”

Section: Introductionmentioning

confidence: 99%

Automating Assessment of the Undiscovered Biosynthetic Potential of Actinobacteria

Tokovenko

Rebets

Luzhetskyy

2016

Preprint

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Background. Biosynthetic potential of Actinobacteria has long been the subject of theoretical estimates. Such an estimate is indeed important as a test of further exploitability of a taxon or group of taxa for new therapeutics. As neither a set of available genomes nor a set of bacterial cultivation methods are static, it makes sense to simplify as much as possible and to improve reproducibility of biosynthetic gene clusters similarity, diversity, and abundance estimations. Results. We have developed a command-line computational pipeline (available at https://bitbucket.org/qmentis/clusterscluster/) that assists in performing empirical (genome-based) assessment of microbial secondary metabolite gene clusters similarity and abundance, and applied it to a set of 208 complete and de-duplicated Actinobacteria genomes. After a brief overview of Actinobacteria biosynthetic potential as compared to other bacterial taxa, we use similarity thresholds derived from 4 pairs of known similar gene clusters to identify up to 40-48% of 3247 gene clusters in our set of genomes as unique. There is no saturation of the cumulative unique gene clusters curve within the examined dataset, and Heap's alpha is 0.129, suggesting an open pan-clustome. We identify and highlight pitfalls and possible improvements of genome-based gene cluster similarity measurements.

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Actinomycetes biosynthetic potential: how to bridge in silico and in vivo?

Cited by 59 publications

References 124 publications

Microbial genome mining for accelerated natural products discovery: is a renaissance in the making?

Microbial genome mining for accelerated natural products discovery: is a renaissance in the making?

Genome mining of Streptomyces ambofaciens

Automating Assessment of the Undiscovered Biosynthetic Potential of Actinobacteria

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