Cofund on Biotechnologies

Shortcut to the carbon efficient microbial production of chemical building blocks from D-xylose

Consortium:

Summary

D-xylose is a major component of lignocellulose and is after D-glucose the most abundant monosaccharide on earth. However, D-xylose cannot be naturally utilised by several industrially relevant microorganisms. On the way to a strong bio-based economy in Europe, this widely available feedstock has to be made accessible for the sustainable microbial synthesis of value-added chemical building blocks to be used in a broad range of applications. The project aims at engineering Corynebacterium glutamicum and Saccharomyces cerevisiae to serve as flexible and carbon efficient microbial cell factories converting D-xylose derived from lignocellulosic material (LCM) into value added products covering diols, lactols and organic acids. Combination of genetic engineering and systems biology are used to demonstrate the potential of a rational system-level approach for metabolic engineering of C. glutamicum and S. cerevisiae. In particular, new fundamental knowledge is generated regarding the impact of industrial hydrolysates on the intracellular dynamics of proteins, metabolites and fluxes as well as global stress responses and production capabilities of the two platform organisms. Subsequently, model-driven optimization approaches are expected to show the feasibility of growth-decoupled production with the newly constructed producer strains on industrial hydrolysates. The project has a high potential for innovative industrial applications, and it is expected to contribute to improve the competitiveness of the European biotechnological industry.

Systematic Rebuilding of Actinomycetes for Natural Product Formation

Consortium:

Summary

There is an urgent need for novel antibiotics to fight life-threatening infections and to counteract the increasing problem of propagating antibiotic resistance. Recently, new molecular genetic and biochemical tools have provided insight into the enormous unexploited genetic pool of environmental microbial biodiversity for new antibiotic compounds. New tools for more efficiently lifting this hidden treasure are needed to strengthen competitiveness of European industry, as well as for a cost-saving medical service for European citizens. The SYSTERACT project aims to develop the model Actinobacterium Streptomyces coelicolor into a 'Superhost' for the efficient production of antibiotic compounds, enabling a faster discovery of new antibiotics from environmental microbial resources. Central to this approach will be an iterative Systems Biology cycle, combining microbiology, genetics, biochemistry, and fermentation technology with predictive modelling. SYSTERACT brings together six partners from four ERASysApp member countries, including four universities, one non-profit research organization, as well as the latter's Technology Transfer Unit. Strong relevant industry is closely connected to the project and supports the research partners in their efforts to develop a reliable new tool by a Systems Biology approach that is useful for a more efficient discovery of new future antibiotics.

Systems analysis of peptide-mediated cell-cell communication in the plant root by in situ sequencing

Consortium:

Summary

Abiotic stress like drought or suboptimal phosphate levels is challenging effective crop growth in many regions over the world. This type of stress reduces crop production by affecting root growth and system architecture that in turn is pivotally controlled by cell-cell communication mechanisms. Manipulation of growth associated cell-cell communication events constitutes a promising strategy to alleviate the adverse growth effects of abiotic stress. As a prerequisite of defining specific interventions, cell-cell communication events have to be understood at molecular detail. Peptide mediated paracrine control has gained increased attention in this context. In order to achieve progress in this field considerable experimental innovation and conceptual developments are required to appropriately study and describe intercellular, cell transcending events in a heterogeneous organ, such as peptide mediated cell-cell communication in roots. This interdisciplinary project aims at developing microfluidic and computational in situ RNA sequencing techniques to study and describe how peptide mediated cell-cell communication regulate root growth and root system architecture under normal and abiotic stress conditions and thereby contribute knowledge to design interventions to alleviate the adverse effect of abiotic stress on plant development and growth.

Optimizing metabolic regulation in yeast production strains for dynamic conditions

Consortium:

Summary

Microbial strains used in biotechnological industry need to produce their biotechnological products at high yield and at the same time they are desired to be robust to the intrinsic nutrient dynamics of large-scale bioreactors, most noticeably to transient limitations of carbon sources and oxygen. The engineering principles for robustness of metabolism to nutrient dynamics are however not yet well understood. The ROBUSTYEAST project aims to reveal these principles for microbial strain improvement in biotechnological applications using a systems biology approach. This will contribute to establishing evolutionary optimization protocols for making microbial production strains robust against dynamic nutrient conditions.

The consortium will study the robustness of Saccharomyces cerevisiae in experiments during the dynamics associated with two cyclic nutrient transitions that are each of major relevance to industry: repeated cycles of glucose and ethanol growth and of aerobic and anaerobic growth. We shall monitor the physiological changes during the evolutionary adaptation of yeast to those transitions, using laboratory-evolution in lab-scale bioreactors (chemostat mode). By combining this data with computational modelling we shall identify the metabolic features that make yeast robust to these industrially relevant condition cycles. The theoretical and computational approaches that the consortium will develop involve optimisation methods applicable to metabolism transiting from one steady state to the next via dynamic regulation.

We shall iterate experiments and modelling to improve our models given experimental data, to identify new measurements critical to improve our understanding, and to finally identify key regulatory mechanisms for a robust metabolism of S. cerevisiae, given changes in glucose, ethanol and oxygen concentrations. The robustness of metabolic regulation under dynamic conditions will be evaluated from the kinetic models, and the regulatory interactions that confer such robustness will be determined

Systems biology platform for the creation of lean-proteome Escherichia coli strains

Consortium:

Summary

Escherichia coli is a well-established and the most widely used organism for the production of recombinant proteins (used in medical and industrial applications, as molecular biology reagents, etc.). Production of proteins is the most resource exhaustive process for the cells and therefore needs to be optimized to achieve maximal productivities. Natural environment of E. coli is much harsher compared to the near optimal growth conditions used in production processes. In order to survive cells produce many native proteins that could be considered unnecessary for the cells in industrial production conditions. In this project we aim to remove the most resource exhaustive unnecessary proteins from the host cells to free up resources for recombinant protein production. We will focus on this by using a novel metabolic modeling approach with constraints of protein production and cell geometry together with proteomics-based host cell physiology characterization. Novel lean-proteome strains with removed unnecessary proteins will be tested for the improved production capacity of several recombinant proteins used in research, industry and diagnostics.