Unlocking the trove of metabolic treasures: activating silent biosynthetic gene clusters in bacteria and fungi

Zhang, Xiafei; Hindra, Hindra; Elliot, Marie A.

doi:10.1016/j.mib.2019.03.003

Cited by 70 publications

(48 citation statements)

References 59 publications

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“…TunPSC04-5I4 were negative for PalA, the presence of silent (not transcribed) biosynthetic gene clusters has received much attention (e.g. 66), thus required evaluation. The biosynthetic gene clusters identified (8 in total) were interrogated for three elements, which we have predicted would be required for PalA biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Uncovering the core microbiome and distributions of palmerolide inSynoicum adareanumacross the Anvers Island archipelago, Antarctica

Murray

Avalon

Bishop

et al. 2020

Preprint

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Section: Discussionmentioning

confidence: 99%

Uncovering the core microbiome and distributions of palmerolide inSynoicum adareanumacross the Anvers Island archipelago, Antarctica

Murray

Avalon

Bishop

et al. 2020

Preprint

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“…This is also the case for pantocin A and B in P. agglomerans EH318 (Wright et al, 2001). Gene clusters that are conditionally expressed are often referred to as silent biosynthetic gene clusters, but can be activated through a variety of means, including manipulation of media composition and other growth conditions (Reen et al, 2015;Zhang et al, 2019). For PNP-1 and PNP-3, altering the composition of the top and base medium in agar overlays led to changes in the size of the zones of inhibition, and in the case of PNP-3, use of a complex medium in both layers caused complete loss of zone of inhibition (Walterson et al, 2014;Williams and Stavrinides, 2020).…”

Section: Discussionmentioning

confidence: 99%

The Integration of Genome Mining, Comparative Genomics, and Functional Genetics for Biosynthetic Gene Cluster Identification

et al. 2020

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Antimicrobial resistance is a worldwide health crisis for which new antibiotics are needed. One strategy for antibiotic discovery is identifying unique antibiotic biosynthetic gene clusters that may produce novel compounds. The aim of this study was to demonstrate how an integrated approach that combines genome mining, comparative genomics, and functional genetics can be used to successfully identify novel biosynthetic gene clusters that produce antimicrobial natural products. Secondary metabolite clusters of an antibiotic producer are first predicted using genome mining tools, generating a list of candidates. Comparative genomic approaches are then used to identify gene suites present in the antibiotic producer that are absent in closely related non-producers. Gene sets that are common to the two lists represent leading candidates, which can then be confirmed using functional genetics approaches. To validate this strategy, we identified the genes responsible for antibiotic production in Pantoea agglomerans B025670, a strain identified in a large-scale bioactivity survey. The genome of B025670 was first mined with antiSMASH, which identified 24 candidate regions. We then used the comparative genomics platform, EDGAR, to identify genes unique to B025670 that were not present in closely related strains with contrasting antibiotic production profiles. The candidate lists generated by antiSMASH and EDGAR were compared with standalone BLAST. Among the common regions was a 14 kb cluster consisting of 14 genes with predicted enzymatic, transport, and unknown functions. Site-directed mutagenesis of the gene cluster resulted in a reduction in antimicrobial activity, suggesting involvement in antibiotic production. An integrated approach that combines genome mining, comparative genomics, and functional genetics yields a powerful, yet simple strategy for identifying potentially novel antibiotics.

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“…The strains used in the ISP2 screen (Section 2.4.1) were screened in parallel with the well-defined M9 media. This allowed variation of the carbon source; different carbon sources can inhibit or stimulate the metabolic pathways that might lead to bioactive secondary metabolites [7,9].…”

Section: Osmac Screen Using M9 Mediamentioning

confidence: 99%

“…Repeated screening of environmental isolates from geographically-related sampling sites frequently delivers molecules that are too similar to known compounds to make commercial development tractable. A further complication is that many of the microbial gene clusters that encode the biosynthetic machinery required to assemble natural product scaffolds are inactive, repressed or 'silent' under standard laboratory culturing conditions [7]. This combination of chemical redundancy and dormant metabolism reduces the likelihood of isolating novel bioactive compounds, even from sizeable culture collections.…”

Section: Introductionmentioning

confidence: 99%

The Bristol Sponge Microbiome Collection: A Unique Repository of Deep-Sea Microorganisms and Associated Natural Products

et al. 2020

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The deep ocean is the largest habitat for life on Earth, though the microorganisms that occupy this unique environmental niche remain largely unexplored. Due to the significant logistical and operational challenges associated with accessing the deep ocean, bioprospecting programmes that seek to generate novel products from marine organisms have, to date, focused predominantly on samples recovered from shallow seas. For this reason, the deep ocean remains a largely untapped resource of novel microbiological life and associated natural products. Here we report the establishment of the Bristol Sponge Microbiome Collection (BISECT), a unique repository of deep-sea microorganisms and associated metabolites isolated from the microbiota of marine sponges, recovered from previously unsurveyed regions of the mid Atlantic Ocean, at depths of 0.3–3 km. An integrated biodiscovery pipeline comprising molecular, genetic, bioinformatic and analytical tools is also described, which is being applied to interrogate this collection. The potential of this approach is illustrated using data reporting our initial efforts to identify antimicrobial natural product lead compounds. Prospects for the use of BISECT to address allied pharmaceutical needs, along with mechanisms of access to the collection are also discussed

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Unlocking the trove of metabolic treasures: activating silent biosynthetic gene clusters in bacteria and fungi

Cited by 70 publications

References 59 publications

Uncovering the core microbiome and distributions of palmerolide inSynoicum adareanumacross the Anvers Island archipelago, Antarctica

Uncovering the core microbiome and distributions of palmerolide inSynoicum adareanumacross the Anvers Island archipelago, Antarctica

The Integration of Genome Mining, Comparative Genomics, and Functional Genetics for Biosynthetic Gene Cluster Identification

The Bristol Sponge Microbiome Collection: A Unique Repository of Deep-Sea Microorganisms and Associated Natural Products

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