Discovery of an Antibacterial Isoindolinone-Containing Tetracyclic Polyketide by Cryptic Gene Activation and Characterization of Its Biosynthetic Gene Cluster

Thong, Wei Li; Shin‐ya, Kazuo; Nishiyama, Makoto; Kuzuyama, Tomohisa

doi:10.1021/acschembio.8b00553

Cited by 15 publications

(12 citation statements)

References 29 publications

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“…Targeted strains are screened by mutations in antibiotic resistance acting on ribosome without special requirement of equipment or genetic background of the strains. Isoindolinomycin (Idm), an unprecedented bioactive polyketide with a novel isoindolinonecontaining tetracyclic skeleton, was discovered by activation of cryptic gene through screening rifampicin-resistant (rif ) mutants from actinobacteria strains (Thong et al, 2018). Piperidamycins production was induced in a gentamicin-resistant mutant of Streptomyces mauvecolor, whereas the wild strain does not produce these metabolites at any detectable level on various media (Hosaka et al, 2009;Baral et al, 2018).…”

Section: Activation the Cryptic Gene Clusters By Ribosome Engineeringmentioning

confidence: 99%

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

Xia

et al. 2020

Front. Microbiol.

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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.

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Section: Activation the Cryptic Gene Clusters By Ribosome Engineeringmentioning

confidence: 99%

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

Xia

et al. 2020

Front. Microbiol.

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“…2). A recent example is the discovery of the polyketide isoindolinomycin through the screening of rifampicin-resistant mutants 77 .…”

Section: Activation Of Silent Pathways Through Ribosome Engineeringmentioning

confidence: 99%

Mining and unearthing hidden biosynthetic potential

2021

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Genetically encoded small molecules (secondary metabolites) play eminent roles in ecological interactions, as pathogenicity factors and as drug leads. Yet, these chemical mediators often evade detection, and the discovery of novel entities is hampered by low production and high rediscovery rates. These limitations may be addressed by genome mining for biosynthetic gene clusters, thereby unveiling cryptic metabolic potential. The development of sophisticated data mining methods and genetic and analytical tools has enabled the discovery of an impressive array of previously overlooked natural products. This review shows the newest developments in the field, highlighting compound discovery from unconventional sources and microbiomes.

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“…Several strategies can be done to activate the silent gene cluster includes co-culture (Onaka, 2017), heterologous expression (Matsuda et al, 2017), ribosome engineering (Thong et al, 2018) and elicitation (Tyurin et al, 2018). (Pettit, 2011); N-acetylglucosamine (NAG) (Rigali et al, 2008;Nazari et al, 2013); and chitin (Nazari et al, 2013).…”

Section: Streptomyces Is a Group Of Filamentousmentioning

confidence: 99%

THE POTENCY OF CHITOSAN AS AN ELICITOR ON ANTIBACTERIAL ACTIVITY OF Streptomyces sp. GMR-22 AGAINST HISTAMINE-PRODUCING BACTERIA

Ikhrami

Widada

Puspita

et al. 2021

Int. J. Biosci. Biotech.

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Streptomyces is a Gram-positive bacteria that produces the largest secondary metabolite compounds. The results of whole-genome sequence analysis showed that Streptomyces can carry more than 30 Biosynthetic Gene Clusters (BGC) encoding secondary metabolites that have the potential to be explored in the exploration for new bioactive compounds. However, not all BGC can be expressed in the laboratory scale and requires a specific activation method. This study aims to explore the potential of chitosan as an elicitor compound to activate and or increase the antibacterial activity of Streptomyces sp. GMR-22 was tested against histamine-producing bacteria (HPB) Morganella morganii TK7 and Citrobacter freundii CK1. Chitosan was added to the fermentation medium with the final concentration of 250, 500, and 750 µg/ml while without the addition of chitosan used as control. Fermentation was carried out for 10 days at room temperature, with constant agitation 200 rpm. The supernatant was separated by centrifugation at 3500 rpm for 15 minutes, then fractionation with ethyl acetate, concentrated by vacuum rotary evaporator, and freeze-dried. The test for antibacterial activity was carried out by the microdilution method with an extract concentration of 100 mg/ml. The test results of the microdilution method showed that the addition of chitosan successfully increases the antibacterial activity with the highest activity shown by the water fraction of 250 µg/ml addition of chitosan which effective in inhibiting the growth of Morganella morganii TK7 and Citrobacter freundii CK1 by 97,29% and 97,92% respectively.

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Discovery of an Antibacterial Isoindolinone-Containing Tetracyclic Polyketide by Cryptic Gene Activation and Characterization of Its Biosynthetic Gene Cluster

Cited by 15 publications

References 29 publications

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

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

Mining and unearthing hidden biosynthetic potential

THE POTENCY OF CHITOSAN AS AN ELICITOR ON ANTIBACTERIAL ACTIVITY OF Streptomyces sp. GMR-22 AGAINST HISTAMINE-PRODUCING BACTERIA

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