DeTOX - Productive whole cell biocatalysis by engineering resistance to toxic products and substrates
Lead Research Organisation:
University of Nottingham
Department Name: Div of Process and Environmental Eng
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
A major challenge in industrial biotechnology & bioenergy is to solve serious problems with yield restrictions due to product or substrate toxicity. Increasing product concentrations by >10-fold would deliver commensurate improvements in revenue from such processes, and is a viable target, given the millimolar product concentrations formed in many proposed bioprocesses at present. This is critical for commercially viable production of bulk & specialty chemicals by living cells, because many of these are toxic & need to be removed rapidly to avoid damage to the intracellular contents & cell membrane. It is also essential for the effective use of lignocellulosic substrates that contain fermentation inhibitors that exert their toxic effects by penetrating the cell. Our objective is to produce host strains with enhanced resistance to a broad range of chemical products & so provide highly-productive chassis for commercial synthetic biology. We will study the mechanisms of chemical toxicity and resistance in E. coli & solventogenic Clostridium spp., both by analyzing cellular responses during bioproduction and by experimental evolution of resistant strains. We will also apply world-leading membrane science (efflux pumps, proteomics, lipidomics & membrane biophysics) to execute novel, rational redesign of cell membranes to enhance resistance. We will combine knowledge of these systems to develop our DeTox strain platform by strain engineering, using synthetic biology standards. The chassis will be tested in small scale replicas of industrial bio-processes, & iteratively redesigned for maximum robustness under process conditions, using models describing cellular responses to toxin exposure. The outcome will be DeTox chassis, to be licensed to our partners, and DeTox gene cassettes, that can be ported to other hosts.
Planned Impact
As described in proposal submitted to IUK
Organisations
- University of Nottingham (Lead Research Organisation)
- Centre for Process Innovation (CPI) (Collaboration)
- University of Sheffield (Collaboration)
- Mitsubishi Chemical Co Ltd (Collaboration)
- Ingenza Ltd (Collaboration)
- University of York (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- UNIVERSITY OF EXETER (Collaboration)
Publications
Drousiotis K
(2023)
Characterization of the l-arabinofuranose-specific GafABCD ABC transporter essential for l-arabinose-dependent growth of the lignocellulose-degrading bacterium Shewanella sp. ANA-3.
in Microbiology (Reading, England)
Goode A
(2021)
Interactions of polymyxin B with lipopolysaccharide-containing membranes.
in Faraday discussions
Hussain R
(2018)
To Boil an Egg: Substrate Binding Affects Critical Stability in Thermal Unfolding of Proteins
in The Journal of Physical Chemistry B
Lanne ABM
(2019)
Molecular recognition of lipopolysaccharide by the lantibiotic nisin.
in Biochimica et biophysica acta. Biomembranes
Meng F
(2021)
Bioethanol from autoclaved municipal solid waste: Assessment of environmental and financial viability under policy contexts
in Applied Energy
Yeh V
(2021)
Solid state NMR of membrane proteins: methods and applications.
in Biochemical Society transactions
Yeh V
(2020)
Membrane Stability in the Presence of Methacrylate Esters.
in Langmuir : the ACS journal of surfaces and colloids
Yeh V
(2022)
The Role of Lipid Chains as Determinants of Membrane Stability in the Presence of Styrene.
in Langmuir : the ACS journal of surfaces and colloids
Yeh V
(2020)
Membrane Protein Structure Determination and Characterisation by Solution and Solid-State NMR.
in Biology
Description | The research has demonstrated the concept of DeTOX vectors as a means of improving tolerance of bacteria to toxic compounds. In particular, styrene has been used as a case study to exemplify the use of omics data in the discovery of the appropriate genes to express via DeTOX vectors. The University of Nottingham has completed the fermentation work associated with this exemplification in a productive collaboration with the University of York and the University of Sheffield within the consortium. |
Exploitation Route | The DeTOX vectors developed during this work help enable sustained production of toxic compounds by microbial cell factories. |
Sectors | Agriculture Food and Drink Chemicals Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
Description | Materials and Manufacturing |
Amount | £1,601,686 (GBP) |
Funding ID | 103761 |
Organisation | Innovate UK |
Sector | Public |
Country | United Kingdom |
Start | 01/2018 |
End | 12/2020 |
Description | CPI |
Organisation | Centre for Process Innovation (CPI) |
Country | United Kingdom |
Sector | Private |
PI Contribution | Nottingham is the Lead partner for ConBioChem and Collaborator on Detox |
Collaborator Contribution | Industrial partner for ConBioChem and Detox |
Impact | None yet |
Start Year | 2016 |
Description | Ingenza |
Organisation | Ingenza Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | Nottingham were partners in the P2P project with Ingenza and Lucite. We also lead the ConBioChem IB catalyst project, for which Ingenza are an industrial partner. We are partners in the Detox IB catalyst project, for which Ingenza are an industrial partner. Ingenza act as industrial hosts for CASE industrial experience placements for our Lucite-sponsored CASE studentships, since they have biotechnology laboratories and Lucite do not. |
Collaborator Contribution | Ingenza and Nottingham are partners within the Lucite project to develop bio-based manufacturing of methylmethacrylate. Ingenza were the lead partner for the P2P project. Ingenza act as industrial hosts for CASE industrial experience placements for our Lucite-sponsored CASE studentships, since they have biotechnology laboratories and Lucite do not. Ingenza are industrial partners in the ConBioChem IB catalyst project (which Nottingham leads) and in the Detox IB catalyst project (in which Nottingham is a partner). |
Impact | GR Eastham, DW Johnson, I Archer, R Carr, J Webb, G Stephens (2015). A Process for Production of Methacrylic Acid and Derivatives Thereof. WO2015022496 Multidisciplinary: Chemistry, microbiology, biochemistry, molecular biology, biotechnology |
Start Year | 2013 |
Description | Mitsubishi Chemical UK |
Organisation | Mitsubishi Chemical Co Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | Nottingham works with Lucite to develop metabolically engineered microorganisms for bio-based methymethacrylate production. We also develop fed-batch and continuous bioprocesses, and methods to solve problems with product toxicity. The work has been done through 7 CASE studentships (Lucite), 2 small projects (Lucite), the P2P grant and our IB catalyst projects, Detox and ConBioChem. |
Collaborator Contribution | Mitsubishi Chemical (previously Lucite International) aim to develop a bio-based route to manufacture methylmethacrylate. Lucite have funded 7 CASE studentships, 2 small projects, have collaborated on the P2P grant and are partners on our IB catalyst projects, Detox and ConBioChem. |
Impact | GR Eastham, G Stephens, A Yiakoumetti (2016). Process for the biological production of methacrylic acid and derivatives thereof. WO2016185211 A1 L Rossoni, SJ Hall, G Eastham, P Licence and G Stephens (2015) The putative mevalonate diphosphate decarboxylase from Picrophilus torridus is in reality a mevalonate-3-kinase with high potential for bio-production of isobutene. Applied and Environmental Microbiology 81, 2625-2634 doi: 10.1128/AEM.04033-14 GR Eastham, DW Johnson, I Archer, R Carr, J Webb, G Stephens (2015). A Process for Production of Methacrylic Acid and Derivatives Thereof. WO2015022496 Multidisciplinary: Chemistry, Biotechnology, Microbiology, Biochemistry, Molecular Biology |
Start Year | 2011 |
Description | University of Cambridge |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Nottingham is Lead partner on ConBioChem and collaborators on Detox projects |
Collaborator Contribution | Collaborators on ConBioChem and Detox |
Impact | None yet |
Start Year | 2016 |
Description | University of Exeter |
Organisation | University of Exeter |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Nottingham is a Collaborator on Detox |
Collaborator Contribution | Collaborator on Detox |
Impact | None yet |
Start Year | 2016 |
Description | University of Sheffield |
Organisation | University of Sheffield |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Nottingham is a Collaborator on Detox |
Collaborator Contribution | Collaborators on Detox |
Impact | None yet |
Start Year | 2016 |
Description | University of York |
Organisation | University of York |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Nottingham is a Collaborator on Detox |
Collaborator Contribution | Lead partner on Detox |
Impact | None yet. |
Start Year | 2016 |