13TSB_TIBio: Synthetic Biology for antibiotic discovery and development
Lead Research Organisation:
University of Manchester
Department Name: Chemistry
Abstract
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Technical Summary
New antibiotics are urgently needed to combat the emerging critical problem of bacteria resistance. The European Centre for Disease Prevention and Control has estimated that antimicrobial resistance costs the EU about 1.5 billion Euros in healthcare and losses productivity each year. The UK government has made clear actions into fighting antimicrobial resistance with a 5 year Antimicrobial Resistance Strategy Report published in September 2013. To tackle this important problem, this project aims to use synthetic biology as a key technology to discover and develop new antibiotics. The project will overcome the common problems associated with antibiotic discovery from natural sources, such as poor understanding of the antibiotic producer, poor growth characteristics, reproducibility, poor yield and a long time to market. Demuris has identified a promising broad-spectrum antibiotic but it is produced in low quantity. The University of Manchester will collaborate with Demuris, an SME expertise in natural products discovery, together with Croda, a large chemicals company with established routes to market, to fully unlocking the potential of this promising broad-spectrum antibiotic using synthetic biology approaches. Bioinformatics and biosynthetic gene cluster refactoring will be used for optimum expression and for introducing additional diversity of the chemical structure. The optimized biosynthetic machinery will then be introduced into Demuris's optimised production host for maximum yield required for commercialisation. In addition, the methods established in this work will be utilised for the activation of novel silent gene clusters identified from the genome sequence of the broad-spectrum antibiotic producer and the products identified and characterised for potential industrial applications.
Planned Impact
N/A
People |
ORCID iD |
| Eriko Takano (Principal Investigator) |
Publications
Breitling R
(2014)
Natural Products - Natural Products: Discourse, Diversity, and Design
Breitling R
(2015)
Synthetic biology advances for pharmaceutical production.
in Current opinion in biotechnology
Carbonell P
(2016)
Bioinformatics for the synthetic biology of natural products: integrating across the Design-Build-Test cycle.
in Natural product reports
Carbonell P
(2016)
SYNBIOCHEM-a SynBio foundry for the biosynthesis and sustainable production of fine and speciality chemicals.
in Biochemical Society transactions
| Description | The genome of a newly identified bacteria has been completed. There are many potential secondary metabolite gene clusters identified from the genome sequence. Attempts have been made to identify some of the compounds with antimicrobial activity produced by this bacteria and also to link the compound to the biosynthesis pathways. Refactoring of the biosynthesis pathway was done to heterologously express the pathways in another bacterium. |
| Exploitation Route | The compounds identified will be commercialised if there are novel antimicrobial activities. The use of synthetic biology approaches, which has been demonstrated in this project, will be applicable to producing other fine chemicals with many properties. The results from this project has now created a BBSRC funded CASE studentship starting from 2018. |
| Sectors | Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| Description | External advisor for European Commission Scientific Committee on Emerging and Newly Identified Health Risks on synthetic biology |
| Geographic Reach | Europe |
| Policy Influence Type | Citation in other policy documents |
| Impact | Made huge impact on the policy for defining Synthetic Biology, identifying the risks for Synthetic Biology and future recommendations in Synthetic Biology risk assessment at a European level. |
| Title | MIBiG |
| Description | Bacteria, fungi and plants produce an enormous variety of small functional molecules with manifold biological activities, e.g., as antibiotics, immunosuppressants, and signaling molecules. The biosynthesis of such molecules is encoded by compact genomic units (biosynthetic gene clusters). Over the past decades, hundreds of biosynthetic gene clusters encoding the biosynthesis of secondary metabolites have been characterized. Although dozens of biosynthetic gene clusters are published and thousands are sequenced annually (with or without their surrounding genome sequence), very little effort has been put into structuring this information. Hence, it is currently very difficult to prioritize gene clusters for experimental characterization, to identify the fundamental architectural principles of biosynthetic gene clusters, to understand which ecological parameters drive their evolution, and to obtain an informative 'parts registry' of building blocks for the synthetic biology of secondary metabolite biosynthesis. Therefore, developing a genomic standard for experimentally characterized biosynthetic gene clusters (e.g., Minimum Information about a BIosynthetic Gene cluster, MIBiG) would be of great value to the field of microbial secondary metabolism. Building on the MIxS standards for ecological and environmental contextualization, information on, e.g., enzyme function, substrate specificities, functional subclusters, regulatory and transport systems, operon structure, chemical moieties of the end compound and its intermediates, biosynthetic precursor compounds, compound bioactivity and molecular targets and compound toxicity could be added to allow cross-linking the information to biochemistry, pharmaceutical properties, genomic structure and ecology. Using the already developed computational pipeline for analysis of biosynthetic gene clusters antiSMASH (http://antismash.secondarymetabolites.org/), which has quickly become a standard in the field, information on characterized biosynthetic gene clusters will be linked to the untapped wealth of thousands of unknown gene clusters that have recently been unearthed by massive genome sequencing efforts. Taken together, this has the potential to guide the characterization of new metabolites by allowing to optimize the sampling of diversity at different levels and to identify the biochemical, genomic and ecological parameters that are key predictors of pharmaceutically relevant biological activities. Moreover, it can transform the unordered pile of literature on secondary metabolites into a structured and annotated catalogue of parts that can be used as building blocks to design new biochemical pathways with synthetic biology. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2015 |
| Provided To Others? | Yes |
| Impact | MIBiG will the better description and contextualization of sequence data, of important sequence elements, with concrete biotechnological applications that will increase the visibility and applicability of the GSC and its mission in the fields of applied microbiology, synthetic biology, natural products chemistry and enzymology. |
| URL | http://gensc.org/projects/mibig/ |
| Description | TSB Demuris |
| Organisation | Demuris Limited |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | The BB/M004910/1 funding was part of a consortium led by Demuris which was applied to and funded by TSB (Innovate UK). Croda is also a partner in this consortium. |
| Collaborator Contribution | Demuris has provided anovel strain and it's genome sequence, also chemical analysis of antimicrobial compounds produced by this strain. |
| Impact | The project is not yet finished and no outputs have been made. New compounds have been discovered and we are now refactoring to produce gentamicin derivative. |
| Start Year | 2014 |
| Description | iGEM participation |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Undergraduate students |
| Results and Impact | Takano has organised the Manchester iGEM team since 2012 with Prof Rainer Breitling. The iGEM competition (International Genetically Engineered Machine competition: https://igem.org/Main_Page) is a prestigious international synthetic biology event, with more than 300 participating teams from international universities (form all over the world), who present their summer research at a Giant Jamboree in Boston. iGEM is a major opportunity for undergraduate students to acquire interdisciplinary and transferable skills and to show their achievements in an international setting. The total number of participants is well over 500 with each team having more that 10 members. Our Manchester teams have been very successful and have achieved a gold medal for four years; in 2016 they won not only the gold medal, but also scooped the special award for 'Best Computational Model' - and were also shortlisted for the 'Best Education and Public Engagement' award. We had very interesting topics from Palm oil production in E. coli to alcohol patch on skin to detect and make aware alcohol consumption. Many discussions involving NGOs(e.g. friends of the earth, green peace, alcohol anonymous) and public institutions (e.g. police, NHS hospitals, FBI) and industry (cheese makers, brewery, confectionery). All of the teams achievements have increased awareness in synthetic biology and sparked many discussion afterwards. We still receive interest for a topic which was done in 2012. More information of the Manchester teams can be found at http://2018.igem.org/Team:Manchester http://2017.igem.org/Team:Manchester http://2016.igem.org/Team:Manchester; http://2015.igem.org/Team:Manchester-Graz; http://2013.igem.org/Team:Manchester |
| Year(s) Of Engagement Activity | 2013,2014,2015,2016,2017,2018 |
| URL | http://2018.igem.org/Team:Manchester |