Activation of microbial secondary metabolic pathways: Avenues and challenges

Baral, Bikash; Akhgari, Amir; Metsä‐Ketelä, Mikko

doi:10.1016/j.synbio.2018.09.001

Cited by 161 publications

(165 citation statements)

References 213 publications

(225 reference statements)

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“…The challenge now, as pointedly stated by Zhang and Moore [93] is how to translate sequence information into chemical reality, and 'to access not just small variations in old chemistry, but completely new chemical scaffolds' . In a valuable discussion of the means of activating such BCGs Baral et al [94], while acknowledging that to date no single superior methodology is available, highlight three approaches for harnessing new natural products: pleiotropic methods aimed at modifying the whole genome; BCG-specific methods, including heterologous expression; and, targeted genome-wide methods that focus on previously identified BCGs of interest.…”

Section: Is Biogeography a Roadmap To Drug Discovery?mentioning

confidence: 99%

Dark, rare and inspirational microbial matter in the extremobiosphere: 16 000 m of bioprospecting campaigns

Bull

Goodfellow

2019

Microbiology

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The rationale of our bioprospecting campaigns is that the extremobiosphere, particularly the deep sea and hyper-arid deserts, harbours undiscovered biodiversity that is likely to express novel chemistry and biocatalysts thereby providing opportunities for therapeutic drug and industrial process development. We have focused on actinobacteria because of their frequent role as keystone species in soil ecosystems and their unrivalled track record as a source of bioactive compounds. Population numbers and diversity of actinobacteria in the extremobiosphere are traditionally considered to be low, although they often comprise the dominant bacterial biota. Recent metagenomic evaluation of 'the uncultured microbial majority' has now revealed enormous taxonomic diversity among 'dark' and 'rare' actinobacteria in samples as diverse as sediments from the depths of the Mariana Trench and soils from the heights of the Central Andes. The application of innovative culture and screening options that emphasize rigorous dereplication at each stage of the analysis, and strain prioritization to identify 'gifted' organisms, have been deployed to detect and characterize bioactive hit compounds and sought-after catalysts from this hitherto untapped resource. The rewards include first-in-a-class chemical entities with novel modes of action, as well as a growing microbial seed bank that represents a potentially enormous source of biotechnological and therapeutic innovation.

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Section: Is Biogeography a Roadmap To Drug Discovery?mentioning

confidence: 99%

Dark, rare and inspirational microbial matter in the extremobiosphere: 16 000 m of bioprospecting campaigns

Bull

Goodfellow

2019

Microbiology

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“…The organization of natural product biosynthetic enzymes into regulated gene clusters has facilitated the identification of biosynthetic gene clusters and enabled the detection of numerous cryptic pathways encoding novel natural products from rapidly accumulating public microbial genome sequence data . Many of these biosynthetic pathways appear silent and under strict regulation, and the metabolites are produced only in response to various environmental stimuli . Natural product biosynthetic gene clusters are much more widespread and more diverse in nature than anticipated and are frequently encountered in microbes not typically associated with natural products .…”

Section: Natural Product Biosynthesis and Comparative Genomicsmentioning

confidence: 99%

A pharmaceutical model for the molecular evolution of microbial natural products

Fewer

Metsä‐Ketelä

2019

The FEBS Journal

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Microbes are talented chemists with the ability to generate tremendously complex and diverse natural products which harbor potent biological activities. Natural products are produced using sets of specialized biosynthetic enzymes encoded by secondary metabolism pathways. Here, we present a two‐step evolutionary model to explain the diversification of biosynthetic pathways that account for the proliferation of these molecules. We argue that the appearance of natural product families has been a slow and infrequent process. The first step led to the original emergence of bioactive molecules and different classes of natural products. However, much of the chemical diversity observed today has resulted from the endless modification of the ancestral biosynthetic pathways. The second step rapidly modulates the pre‐existing biological activities to increase their potency and to adapt to changing environmental conditions. We highlight the importance of enzyme promiscuity in this process, as it facilitates both the incorporation of horizontally transferred genes into secondary metabolic pathways and the functional differentiation of proteins to catalyze novel chemistry. We provide examples where single point mutations or recombination events have been sufficient for new enzymatic activities to emerge. A unique feature in the evolution of microbial secondary metabolism is that gene duplication is not essential but offers opportunities to synthesize more complex metabolites. Microbial natural products are highly important for the pharmaceutical industry due to their unique bioactivities. Therefore, understanding the natural mechanisms leading to the formation of diverse metabolic pathways is vital for future attempts to utilize synthetic biology for the generation of novel molecules.

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“…The transcription processes of BGCs are usually modulated by specific regulatory gene clusters, including activators and repressors, which activate or repress biosynthesis, respectively. The identification of PSRs genes offers possibility to activate the desired BGCs either by inactivation of the repressor or overexpression of the activator genes (Baral et al, 2018).…”

Section: Activation Of the Cryptic Gene Clusters By Manipulation Of Tmentioning

confidence: 99%

“…LuxR superfamily is another predominant class of regulators associated with quorum sensing (Baral et al, 2018). Contrary to the TetR family, LuxR-like proteins usually act as activators during secondary metabolic regulation.…”

Section: Activation Of the Cryptic Gene Clusters By Manipulation Of Tmentioning

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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Activation of microbial secondary metabolic pathways: Avenues and challenges

Cited by 161 publications

References 213 publications

Dark, rare and inspirational microbial matter in the extremobiosphere: 16 000 m of bioprospecting campaigns

Dark, rare and inspirational microbial matter in the extremobiosphere: 16 000 m of bioprospecting campaigns

A pharmaceutical model for the molecular evolution of microbial natural products

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

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