Metabolic engineering with systems biology tools to optimize production of prokaryotic secondary metabolites

Kim, Hyun Uk; Charusanti, Pep; Lee, Sang Yup; Weber, Tilmann

doi:10.1039/c6np00019c

Cited by 55 publications

(35 citation statements)

References 77 publications

(107 reference statements)

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“…A particular example concerns secondary metabolites, which are often derived from non-model organisms, thus making the corresponding biosynthetic pathways poorly characterized especially with the host being difficult to genetically engineer with traditional tools. In this example, one could either consider using CRISPR technology to integrate this large pathway into a well characterized organism, or, directly genetically engineer the host organism to further enhance the product formation or elucidate its idiosyncrasies [52,75].…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Advancing biotechnology with CRISPR/Cas9: recent applications and patent landscape

Ferreira

David

Nielsen

2018

Journal of Industrial Microbiology and Biotechnology

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Clustered regularly interspaced short palindromic repeats (CRISPR) is poised to become one of the key scientific discoveries of the twenty-first century. Originating from prokaryotic and archaeal immune systems to counter phage invasions, CRISPRbased applications have been tailored for manipulating a broad range of living organisms. From the different elucidated types of CRISPR mechanisms, the type II system adapted from Streptococcus pyogenes has been the most exploited as a tool for genome engineering and gene regulation. In this review, we describe the different applications of CRISPR/Cas9 technology in the industrial biotechnology field. Next, we detail the current status of the patent landscape, highlighting its exploitation through different companies, and conclude with future perspectives of this technology.

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Section: Conclusion and Discussionmentioning

confidence: 99%

Advancing biotechnology with CRISPR/Cas9: recent applications and patent landscape

Ferreira

David

Nielsen

2018

Journal of Industrial Microbiology and Biotechnology

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“…Knowledge-driven metabolic engineering of bacterial communities is an emerging field which might shed light on some of the most puzzling biological questions regarding clinical problems (e.g., drug–bacteria interactions; Ye et al, 2014), industrial production design (e.g., enhancing secondary metabolites production; Kim et al, 2016), and environmental safety/health (e.g., bioremediation; Rein et al, 2016) ( Figure 1 ). Several efforts have been directed at characterizing the interactions between bacterial pathogens and their host, aiming at designing probiotic formulations to recover damaged communities (such as the human gut microbiota following C. difficile infection; Buffie et al, 2015), or able to directly suppress pathogen proliferation (Buffie et al, 2015).…”

Section: Strengths and Weaknesses Of Community Modelsmentioning

confidence: 99%

Perspectives and Challenges in Microbial Communities Metabolic Modeling

et al. 2017

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Bacteria have evolved to efficiently interact each other, forming complex entities known as microbial communities. These “super-organisms” play a central role in maintaining the health of their eukaryotic hosts and in the cycling of elements like carbon and nitrogen. However, despite their crucial importance, the mechanisms that influence the functioning of microbial communities and their relationship with environmental perturbations are obscure. The study of microbial communities was boosted by tremendous advances in sequencing technologies, and in particular by the possibility to determine genomic sequences of bacteria directly from environmental samples. Indeed, with the advent of metagenomics, it has become possible to investigate, on a previously unparalleled scale, the taxonomical composition and the functional genetic elements present in a specific community. Notwithstanding, the metagenomic approach per se suffers some limitations, among which the impossibility of modeling molecular-level (e.g., metabolic) interactions occurring between community members, as well as their effects on the overall stability of the entire system. The family of constraint-based methods, such as flux balance analysis, has been fruitfully used to translate genome sequences in predictive, genome-scale modeling platforms. Although these techniques have been initially developed for analyzing single, well-known model organisms, their recent improvements allowed engaging in multi-organism in silico analyses characterized by a considerable predictive capability. In the face of these advances, here we focus on providing an overview of the possibilities and challenges related to the modeling of metabolic interactions within a bacterial community, discussing the feasibility and the perspectives of this kind of analysis in the (near) future.

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“…After decades of investigation, actinomycetes still remain one of the most important sources for the discovery of novel antibiotics . Most of the antibiotics are synthesized by a set of specialized enzymes in secondary metabolism of these soil bacteria, for example, nonribosomal peptide synthetases and polyketide synthases, and a few tailoring enzymes . In most bacteria, these enzymes are encoded by genes clustered together in genome, often called as a biosynthetic gene cluster (BGC).…”

Section: Introductionmentioning

confidence: 99%

Genome‐Scale Metabolic Reconstruction of Actinomycetes for Antibiotics Production

Mohite

Weber

Kim

et al. 2018

Biotechnology Journal

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Systems biology approaches are increasingly applied to explore the potential of actinomycetes for the discovery and optimal production of antibiotics. In particular, genome-scale metabolic models (GEMs) of various actinomycetes are reconstructed at a faster rate in recent years, which has opened avenues to study interaction between primary and secondary metabolism at systems level, and to predict gene manipulation targets for overproduction of important antibiotics. Here, the status of actinomycetes' GEMs and their applications for designing antibiotics-overproducing strains are presented. Despite advances in the practice of GEM reconstruction, actinomycetes' GEMs still remain incomplete in describing a full set of biosynthetic pathways of secondary metabolites. As to the GEM-based strategies, various simulation methods are deployed to better describe secondary metabolism by introducing changes in constraints and/or objective function as well as by using omics data. Gene manipulation targeting algorithms developed for metabolic engineering of model organisms have also been actively applied to actinomycetes for the antibiotics production. Further consideration of computational resources dedicated to secondary metabolites in addition with automated GEM reconstruction tools will further upgrade GEMs of actinomycetes for antibiotics discovery and development.

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Metabolic engineering with systems biology tools to optimize production of prokaryotic secondary metabolites

Abstract: This Highlight examines current status of metabolic engineering and systems biology tools deployed for the optimal production of prokaryotic secondary metabolites.

Cited by 55 publications

References 77 publications

Advancing biotechnology with CRISPR/Cas9: recent applications and patent landscape

Advancing biotechnology with CRISPR/Cas9: recent applications and patent landscape

Perspectives and Challenges in Microbial Communities Metabolic Modeling

Genome‐Scale Metabolic Reconstruction of Actinomycetes for Antibiotics Production

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