Activating secondary metabolism with stress and chemicals

Yoon, Vanessa; Nodwell, Justin R.

doi:10.1007/s10295-013-1387-y

Cited by 104 publications

(89 citation statements)

References 76 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: Discussionmentioning

confidence: 66%

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: Discussionmentioning

confidence: 66%

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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“…Efforts to activate secondary metabolic genes have revealed rare, overlooked and, in some cases, novel antimicrobials thus underscoring the importance of studying this secondary metabolic 'dark matter'. [11][12][13] Additional approaches 14,15 to finding new bioactive chemical matter involve exploring actinobacteria from novel ecological niches, [16][17][18][19] screening unculturable bacteria (for example, teixobactin) 20 and screening for new biological activities, such as the inhibition of antibiotic resistance (for example, aspergillomarasmine A). 21 There is also considerable value in naturally-occurring congeners of known compounds.…”

Section: Introductionmentioning

confidence: 99%

13-Deoxytetrodecamycin, a new tetronate ring-containing antibiotic that is active against multidrug-resistant Staphylococcus aureus

et al. 2015

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WAC04657 is a wild-isolate Streptomyces that has antibiotic activities against multidrug-resistant Gram-negative and Gram-positive pathogens. From a solid-agar culture of this organism we isolated 13-deoxytetrodecamycin, a novel antibacterial molecule. It is one of at least three distinct antimicrobial compounds produced by this strain. The molecule has the molecular formula C 18 H 22 O 5 and is related to the previously discovered compound tetrodecamycin. 13-Deoxytetrodecamycin has potent bioactivity against Gram-positive pathogens including multidrug-resistant Staphylococcus aureus.

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“…NMR analysis of 10 in CD 3 OD at 298 K (Figure 2 B) revealed instantly significant similarities to undecylprodigiosin (8) and streptorubin B (9). Six proton signals at d = 6.2-7.1 ppm corresponding to seven pyrrole protons and an intense signal for alkyl protons (d = 0.76-1.47 ppm) were observed, with the latter matching two undecyl side chains.…”

mentioning

confidence: 97%

“…Biotic and abiotic factors influence the microorganisms, leading to morphological and metabolic changes. [9][10][11][12] The influence of such environmental factors can be studied in the laboratory, for example, by co-cultivation, [13,14] or by addition of antibiotics in subinhibitory concentrations, [10,15] signaling compounds, [9] or transition metal ions [16] such as Sc 3 + ions [17,18] or Co 2 + ions [19,20] into the growth medium. Here, we studied the adaptation of S. coelicolor M145 (the source strain for the genome sequencing, not containing the plasmids SCP1 and SCP2 compared to S. coelicolor A3(2)) [21] to suboptimal growth caused by transition metal ions that induced the formation of diverse phenotypes ( Figure S1 in the Supporting Information), in particular a red phenotype (Figure S1 C in the Supporting Information) in S. coelicolor M145.…”

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confidence: 99%

Divalent Transition‐Metal‐Ion Stress Induces Prodigiosin Biosynthesis in Streptomyces coelicolor M145: Formation of Coeligiosins

Morgenstern

Paetz

Behrend

et al. 2015

Chemistry A European J

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The bacterium Streptomyces coelicolor M145 reacts to transition-metal-ion stress with myriad growth responses, leading to different phenotypes. In particular, in the presence of Co 2 + ions (0.7 mm) S. coelicolor consistently produced a red phenotype. This phenotype, when compared to the wild type, differed strongly in its production of volatile compounds as well as high molecular weight secondary metabolites. LC-MS analysis revealed that in the red phenotype the production of the prodigiosins, undecylprodigiosin and streptorubin B, was strongly induced and, in addition, several intense signals appeared in the LC-MS chromatogram. Using LC-MS/MS and NMR spectroscopy, two new prodigiosin derivatives were identified, that is, coeligiosin A and B, which contained an additional undecylpyrrolyl side chain attached to the central carbon of the tripyrrole ring system of undecylprodigiosin or streptorubin B. This example demonstrates that environmental factors such as heavy metal ion stress can not only induce the production of otherwise not observed metabolites from so called sleeping genes but alter the products from well-studied biosynthetic pathways.In their natural environment, microorganisms such as Actinomyces have to cope with changing and sometimes adverse conditions. Microorganisms not only rapidly adapt under evolutionary pressure [1] but their genomes contain a great repertoire of secondary metabolite genes [2] that can ensure their survival.Actinomyces are most well-known for their secondary metabolites, such as polyketides or non-ribosomal peptides, many of which turned out to be of invaluable pharmaceutical use, for example, as antibiotics. [3] The variation of fermentation conditions has been intensively used in order to optimize the production of secondary metabolites in biotechnological processes.[4] Bode et al. systematically varied growth conditions in order to induce the formation of diverse secondary metabolites in a selected Streptomyces strain and termed their approach OSMAC (one strain many compounds).[5] With the genome sequencing of many Actinomyces such as the model Streptomycete Streptomyces coelicolor A3(2), [6] it became evident that these antibiotic producers comprise a lot more secondary metabolite gene clusters than secondary metabolites that have been identified from them. [2,7] Clearly, the maintenance of secondary metabolite gene clusters and their formation is costly for the producing strains.[8] In contrast to laboratory cultivation under optimized growth conditions, in their natural environment microorganisms have to cope with biotic and abiotic stress factors, for example, competition for space and nutrients. In such scenarios secondary metabolites are likely specifically and flexibly produced to ensure survival under varying and challenging growth conditions. In nature, therefore, microorganisms most likely produce secondary metabolites from "silent gene clusters" to react to their environment. Biotic and abiotic factors influence the microorganisms, leading to morpholo...

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Activating secondary metabolism with stress and chemicals

Cited by 104 publications

References 76 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

13-Deoxytetrodecamycin, a new tetronate ring-containing antibiotic that is active against multidrug-resistant Staphylococcus aureus

Divalent Transition‐Metal‐Ion Stress Induces Prodigiosin Biosynthesis in Streptomyces coelicolor M145: Formation of Coeligiosins

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