Project acronym 14Constraint
Project Radiocarbon constraints for models of C cycling in terrestrial ecosystems: from process understanding to global benchmarking
Researcher (PI) Susan Trumbore
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Advanced Grant (AdG), PE10, ERC-2015-AdG
Summary The overall goal of 14Constraint is to enhance the availability and use of radiocarbon data as constraints for process-based understanding of the age distribution of carbon in and respired by soils and ecosystems. Carbon enters ecosystems by a single process, photosynthesis. It returns by a range of processes that depend on plant allocation and turnover, the efficiency and rate of litter decomposition and the mechanisms stabilizing C in soils. Thus the age distribution of respired CO2 and the age of C residing in plants, litter and soils are diagnostic properties of ecosystems that provide key constraints for testing carbon cycle models. Radiocarbon, especially the transit of ‘bomb’ 14C created in the 1960s, is a powerful tool for tracing C exchange on decadal to centennial timescales. 14Constraint will assemble a global database of existing radiocarbon data (WP1) and demonstrate how they can constrain and test ecosystem carbon cycle models. WP2 will fill data gaps and add new data from sites in key biomes that have ancillary data sufficient to construct belowground C and 14C budgets. These detailed investigations will focus on the role of time lags caused in necromass and fine roots, as well as the dynamics of deep soil C. Spatial extrapolation beyond the WP2 sites will require sampling along global gradients designed to explore the relative roles of mineralogy, vegetation and climate on the age of C in and respired from soil (WP3). Products of this 14Constraint will include the first publicly available global synthesis of terrestrial 14C data, and will add over 5000 new measurements. This project is urgently needed before atmospheric 14C levels decline to below 1950 levels as expected in the next decade.
Summary
The overall goal of 14Constraint is to enhance the availability and use of radiocarbon data as constraints for process-based understanding of the age distribution of carbon in and respired by soils and ecosystems. Carbon enters ecosystems by a single process, photosynthesis. It returns by a range of processes that depend on plant allocation and turnover, the efficiency and rate of litter decomposition and the mechanisms stabilizing C in soils. Thus the age distribution of respired CO2 and the age of C residing in plants, litter and soils are diagnostic properties of ecosystems that provide key constraints for testing carbon cycle models. Radiocarbon, especially the transit of ‘bomb’ 14C created in the 1960s, is a powerful tool for tracing C exchange on decadal to centennial timescales. 14Constraint will assemble a global database of existing radiocarbon data (WP1) and demonstrate how they can constrain and test ecosystem carbon cycle models. WP2 will fill data gaps and add new data from sites in key biomes that have ancillary data sufficient to construct belowground C and 14C budgets. These detailed investigations will focus on the role of time lags caused in necromass and fine roots, as well as the dynamics of deep soil C. Spatial extrapolation beyond the WP2 sites will require sampling along global gradients designed to explore the relative roles of mineralogy, vegetation and climate on the age of C in and respired from soil (WP3). Products of this 14Constraint will include the first publicly available global synthesis of terrestrial 14C data, and will add over 5000 new measurements. This project is urgently needed before atmospheric 14C levels decline to below 1950 levels as expected in the next decade.
Max ERC Funding
2 283 747 €
Duration
Start date: 2016-12-01, End date: 2021-11-30
Project acronym 2D-CHEM
Project Two-Dimensional Chemistry towards New Graphene Derivatives
Researcher (PI) Michal Otyepka
Host Institution (HI) UNIVERZITA PALACKEHO V OLOMOUCI
Call Details Consolidator Grant (CoG), PE5, ERC-2015-CoG
Summary The suite of graphene’s unique properties and applications can be enormously enhanced by its functionalization. As non-covalently functionalized graphenes do not target all graphene’s properties and may suffer from limited stability, covalent functionalization represents a promising way for controlling graphene’s properties. To date, only a few well-defined graphene derivatives have been introduced. Among them, fluorographene (FG) stands out as a prominent member because of its easy synthesis and high stability. Being a perfluorinated hydrocarbon, FG was believed to be as unreactive as the two-dimensional counterpart perfluoropolyethylene (Teflon®). However, our recent experiments showed that FG is not chemically inert and can be used as a viable precursor for synthesizing graphene derivatives. This surprising behavior indicates that common textbook grade knowledge cannot blindly be applied to the chemistry of 2D materials. Further, there might be specific rules behind the chemistry of 2D materials, forming a new chemical discipline we tentatively call 2D chemistry. The main aim of the project is to explore, identify and apply the rules of 2D chemistry starting from FG. Using the knowledge gained of 2D chemistry, we will attempt to control the chemistry of various 2D materials aimed at preparing stable graphene derivatives with designed properties, e.g., 1-3 eV band gap, fluorescent properties, sustainable magnetic ordering and dispersability in polar media. The new graphene derivatives will be applied in sensing, imaging, magnetic delivery and catalysis and new emerging applications arising from the synergistic phenomena are expected. We envisage that new applications will be opened up that benefit from the 2D scaffold and tailored properties of the synthesized derivatives. The derivatives will be used for the synthesis of 3D hybrid materials by covalent linking of the 2D sheets joined with other organic and inorganic molecules, nanomaterials or biomacromolecules.
Summary
The suite of graphene’s unique properties and applications can be enormously enhanced by its functionalization. As non-covalently functionalized graphenes do not target all graphene’s properties and may suffer from limited stability, covalent functionalization represents a promising way for controlling graphene’s properties. To date, only a few well-defined graphene derivatives have been introduced. Among them, fluorographene (FG) stands out as a prominent member because of its easy synthesis and high stability. Being a perfluorinated hydrocarbon, FG was believed to be as unreactive as the two-dimensional counterpart perfluoropolyethylene (Teflon®). However, our recent experiments showed that FG is not chemically inert and can be used as a viable precursor for synthesizing graphene derivatives. This surprising behavior indicates that common textbook grade knowledge cannot blindly be applied to the chemistry of 2D materials. Further, there might be specific rules behind the chemistry of 2D materials, forming a new chemical discipline we tentatively call 2D chemistry. The main aim of the project is to explore, identify and apply the rules of 2D chemistry starting from FG. Using the knowledge gained of 2D chemistry, we will attempt to control the chemistry of various 2D materials aimed at preparing stable graphene derivatives with designed properties, e.g., 1-3 eV band gap, fluorescent properties, sustainable magnetic ordering and dispersability in polar media. The new graphene derivatives will be applied in sensing, imaging, magnetic delivery and catalysis and new emerging applications arising from the synergistic phenomena are expected. We envisage that new applications will be opened up that benefit from the 2D scaffold and tailored properties of the synthesized derivatives. The derivatives will be used for the synthesis of 3D hybrid materials by covalent linking of the 2D sheets joined with other organic and inorganic molecules, nanomaterials or biomacromolecules.
Max ERC Funding
1 831 103 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym ACCI
Project Atmospheric Chemistry-Climate Interactions
Researcher (PI) John Adrian Pyle
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Advanced Grant (AdG), PE10, ERC-2010-AdG_20100224
Summary Global change involves a large number of complex interactions between various earth system processes. In the atmosphere, one component of the earth system, there are crucial feedbacks between physical, chemical and biological processes. Thus many of the drivers of climate change depend on chemical processes in the atmosphere including, in addition to ozone and water vapour, methane, nitrous oxide, the halocarbons as well as a range of inorganic and organic aerosols. The link between chemistry and climate is two-way and changes in climate can influence atmospheric chemistry processes in a variety of ways.
Previous studies have looked at these interactions in isolation but the time is now right for more comprehensive studies. The crucial contribution that will be made here is in improving our understanding of the processes within this complex system. Process understanding has been the hallmark of my previous work. The earth system scope here will be ambitiously wide but with a similar drive to understand fundamental processes.
The ambitious programme of research is built around four interrelated questions using new state-of-the-art modelling tools: How will the composition of the stratosphere change in the future, given changes in the concentrations of ozone depleting substances and greenhouse gases? How will these changes in the stratosphere affect tropospheric composition and climate? How will the composition of the troposphere change in the future, given changes in the emissions of ozone precursors and greenhouse gases? How will these changes in the troposphere affect the troposphere-stratosphere climate system?
ACCI will break new ground in bringing all of these questions into a single modelling and diagnostic framework, enabling interrelated questions to be answered which should radically improve our overall projections for global change.
Summary
Global change involves a large number of complex interactions between various earth system processes. In the atmosphere, one component of the earth system, there are crucial feedbacks between physical, chemical and biological processes. Thus many of the drivers of climate change depend on chemical processes in the atmosphere including, in addition to ozone and water vapour, methane, nitrous oxide, the halocarbons as well as a range of inorganic and organic aerosols. The link between chemistry and climate is two-way and changes in climate can influence atmospheric chemistry processes in a variety of ways.
Previous studies have looked at these interactions in isolation but the time is now right for more comprehensive studies. The crucial contribution that will be made here is in improving our understanding of the processes within this complex system. Process understanding has been the hallmark of my previous work. The earth system scope here will be ambitiously wide but with a similar drive to understand fundamental processes.
The ambitious programme of research is built around four interrelated questions using new state-of-the-art modelling tools: How will the composition of the stratosphere change in the future, given changes in the concentrations of ozone depleting substances and greenhouse gases? How will these changes in the stratosphere affect tropospheric composition and climate? How will the composition of the troposphere change in the future, given changes in the emissions of ozone precursors and greenhouse gases? How will these changes in the troposphere affect the troposphere-stratosphere climate system?
ACCI will break new ground in bringing all of these questions into a single modelling and diagnostic framework, enabling interrelated questions to be answered which should radically improve our overall projections for global change.
Max ERC Funding
2 496 926 €
Duration
Start date: 2011-05-01, End date: 2017-04-30
Project acronym AEDNA
Project Amorphous and Evolutionary DNA Nanotechnology
Researcher (PI) Friedrich SIMMEL
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), PE5, ERC-2015-AdG
Summary Amorphous and evolutionary DNA nanotechnology (AEDNA) explores novel conceptual directions and applications for DNA nanotechnology, which are based on intelligent, DNA-programmed soft hybrid materials, and the utilization of evolutionary principles for the optimization of nucleic acid nanocomponents.
Amorphous DNA nanotechnology first aims at the creation of cell-sized, DNA-programmed microgels – DNA cells – with sensor, computation, communication, and actuator functions. Interacting DNA cells will be arranged into chemical cell consortia and artificial tissues using microfluidics, micromanipulation and 3D bioprinting techniques. Spatially distributed chemical circuits will then be utilized to establish collective behaviors such as quorum sensing, pattern formation, and self-differentiation within these consortia and tissues. The approach will be further scaled up to produce multicomponent DNA gel compositions that become active and differentiate upon mixing.
In evolutionary nanotechnology, techniques derived from directed molecular evolution experiments will be applied to optimize the arrangement of functional nucleic acids on DNA and RNA nanoscaffolds. Compartmentalization and microfluidics will be utilized to screen for nucleic acid nanostructures capable of superstructure formation, and also for the development of ligand-sensitive components for molecular programming. An evolutionary approach will then be applied to amorphous DNA cells, resulting in DNA cell populations which contain individuals with different molecular identities.
The proposal will pave the way for the creation of macroscopic materials with DNA-programmed intelligence, resulting in novel applications for DNA nanotechnology and molecular programming in diverse fields such as environmental and biological sensing, biocatalysis, smart adaptive materials, and soft robotics.
Summary
Amorphous and evolutionary DNA nanotechnology (AEDNA) explores novel conceptual directions and applications for DNA nanotechnology, which are based on intelligent, DNA-programmed soft hybrid materials, and the utilization of evolutionary principles for the optimization of nucleic acid nanocomponents.
Amorphous DNA nanotechnology first aims at the creation of cell-sized, DNA-programmed microgels – DNA cells – with sensor, computation, communication, and actuator functions. Interacting DNA cells will be arranged into chemical cell consortia and artificial tissues using microfluidics, micromanipulation and 3D bioprinting techniques. Spatially distributed chemical circuits will then be utilized to establish collective behaviors such as quorum sensing, pattern formation, and self-differentiation within these consortia and tissues. The approach will be further scaled up to produce multicomponent DNA gel compositions that become active and differentiate upon mixing.
In evolutionary nanotechnology, techniques derived from directed molecular evolution experiments will be applied to optimize the arrangement of functional nucleic acids on DNA and RNA nanoscaffolds. Compartmentalization and microfluidics will be utilized to screen for nucleic acid nanostructures capable of superstructure formation, and also for the development of ligand-sensitive components for molecular programming. An evolutionary approach will then be applied to amorphous DNA cells, resulting in DNA cell populations which contain individuals with different molecular identities.
The proposal will pave the way for the creation of macroscopic materials with DNA-programmed intelligence, resulting in novel applications for DNA nanotechnology and molecular programming in diverse fields such as environmental and biological sensing, biocatalysis, smart adaptive materials, and soft robotics.
Max ERC Funding
2 157 698 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym AMOPROX
Project Quantifying Aerobic Methane Oxidation in the Ocean: Calibration and palaeo application of a novel proxy
Researcher (PI) Helen Marie Talbot
Host Institution (HI) UNIVERSITY OF NEWCASTLE UPON TYNE
Call Details Starting Grant (StG), PE10, ERC-2010-StG_20091028
Summary Methane, a key greenhouse gas, is cycled by microorganisms via two pathways, aerobically and anaerobically. Research on the
marine methane cycle has mainly concentrated on anaerobic processes. Recent biomarker work has provided compelling
evidence that aerobic methane oxidation (AMO) can play a more significant role in cycling methane emitted from sediments than
previously considered. AMO, however, is not well studied requiring novel proxies that can be applied to the sedimentary record. A
group of complex lipids biosynthesised by aerobic methanotrophs known as aminobacteriohopanepolyols represent an ideal target
for developing such poxies. Recently BHPs have been identified in a wide range of modern and recent environments including a
continuous record from the Congo deep sea fan spanning the last 1.2 million years.
In this integrated study, the regulation and expression of BHP will be investigated and calibrated against environmental variables
including temperature, pH, salinity and, most importantly, methane concentrations. The work program has three complementary
strands. (1) Pure culture and sedimentary microcosm experiments providing an approximation to natural conditions. (2) Calibration
of BHP signatures in natural marine settings (e.g. cold seeps, mud volcanoes, pockmarks) against measured methane gradients.
(3) Application of this novel approach to the marine sedimentary record to approximate methane fluxes in the past, explore the age
and bathymetric limits of this novel molecular proxy, and identify and potentially 14C date palaeo-pockmarks structures. Crucial to
the success is also the refinement of the analytical protocols to improve both accuracy and sensitivity, using a more sensitive
analytical instrument (triple-quadrupole mass spectrometer).
Summary
Methane, a key greenhouse gas, is cycled by microorganisms via two pathways, aerobically and anaerobically. Research on the
marine methane cycle has mainly concentrated on anaerobic processes. Recent biomarker work has provided compelling
evidence that aerobic methane oxidation (AMO) can play a more significant role in cycling methane emitted from sediments than
previously considered. AMO, however, is not well studied requiring novel proxies that can be applied to the sedimentary record. A
group of complex lipids biosynthesised by aerobic methanotrophs known as aminobacteriohopanepolyols represent an ideal target
for developing such poxies. Recently BHPs have been identified in a wide range of modern and recent environments including a
continuous record from the Congo deep sea fan spanning the last 1.2 million years.
In this integrated study, the regulation and expression of BHP will be investigated and calibrated against environmental variables
including temperature, pH, salinity and, most importantly, methane concentrations. The work program has three complementary
strands. (1) Pure culture and sedimentary microcosm experiments providing an approximation to natural conditions. (2) Calibration
of BHP signatures in natural marine settings (e.g. cold seeps, mud volcanoes, pockmarks) against measured methane gradients.
(3) Application of this novel approach to the marine sedimentary record to approximate methane fluxes in the past, explore the age
and bathymetric limits of this novel molecular proxy, and identify and potentially 14C date palaeo-pockmarks structures. Crucial to
the success is also the refinement of the analytical protocols to improve both accuracy and sensitivity, using a more sensitive
analytical instrument (triple-quadrupole mass spectrometer).
Max ERC Funding
1 496 392 €
Duration
Start date: 2010-11-01, End date: 2016-04-30
Project acronym AMPCAT
Project Self-Amplifying Stereodynamic Catalysts in Enantioselective Catalysis
Researcher (PI) Oliver Trapp
Host Institution (HI) RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG
Call Details Starting Grant (StG), PE5, ERC-2010-StG_20091028
Summary Think about an enantioselective catalyst, which can switch its enantioselectivity and which can be imprinted and provides self-amplification by its own chiral reaction product. Think about a catalyst, which can be fine-tuned for efficient stereoselective synthesis of drugs and other materials, e.g. polymers.
Highly promising reactions such as enantioselective autocatalysis (Soai reaction) and chiral catalysts undergoing dynamic interconversions, e.g. BIPHEP ligands, are still not understood. Their application is very limited to a few compounds, which opens the field for novel investigations.
I propose the development of a smart or switchable chiral ligand undergoing dynamic interconversions. These catalysts will be tuned by their reaction product, and this leads to self-amplification of one of the stereoisomers. I propose a novel fundamental mechanism which has the potential to overcome the limitations of the Soai reaction, exploiting the full potential of enantioselective catalysis.
As representatives of enantioselective self-amplifying stereodynamic catalysts a novel class of diazirine based ligands will be developed, their interconversion barrier is tuneable between 80 and 130 kJ/mol. Specifically, following areas will be explored:
1. Investigation of the kinetics and thermodynamics of the Soai reaction as a model reaction by analysis of large sets of kinetic data.
2. Ligands with diaziridine moieties with flexible structure will be designed and investigated, to control the enantioselectivity.
3. Design of a ligand receptor group for product interaction to switch the chirality. Study of self-amplification in enantioselective processes.
4. Enantioselective hydrogenations, Diels-Alder reactions, epoxidations and reactions generating multiple stereocenters will be targeted.
Summary
Think about an enantioselective catalyst, which can switch its enantioselectivity and which can be imprinted and provides self-amplification by its own chiral reaction product. Think about a catalyst, which can be fine-tuned for efficient stereoselective synthesis of drugs and other materials, e.g. polymers.
Highly promising reactions such as enantioselective autocatalysis (Soai reaction) and chiral catalysts undergoing dynamic interconversions, e.g. BIPHEP ligands, are still not understood. Their application is very limited to a few compounds, which opens the field for novel investigations.
I propose the development of a smart or switchable chiral ligand undergoing dynamic interconversions. These catalysts will be tuned by their reaction product, and this leads to self-amplification of one of the stereoisomers. I propose a novel fundamental mechanism which has the potential to overcome the limitations of the Soai reaction, exploiting the full potential of enantioselective catalysis.
As representatives of enantioselective self-amplifying stereodynamic catalysts a novel class of diazirine based ligands will be developed, their interconversion barrier is tuneable between 80 and 130 kJ/mol. Specifically, following areas will be explored:
1. Investigation of the kinetics and thermodynamics of the Soai reaction as a model reaction by analysis of large sets of kinetic data.
2. Ligands with diaziridine moieties with flexible structure will be designed and investigated, to control the enantioselectivity.
3. Design of a ligand receptor group for product interaction to switch the chirality. Study of self-amplification in enantioselective processes.
4. Enantioselective hydrogenations, Diels-Alder reactions, epoxidations and reactions generating multiple stereocenters will be targeted.
Max ERC Funding
1 452 000 €
Duration
Start date: 2010-12-01, End date: 2016-05-31
Project acronym ANaPSyS
Project Artificial Natural Products System Synthesis
Researcher (PI) Tanja Gaich
Host Institution (HI) UNIVERSITAT KONSTANZ
Call Details Starting Grant (StG), PE5, ERC-2015-STG
Summary "Traditionally, natural products are classified into ""natural product families"". Within a family all congeners display specific structure elements, owing to their common biosynthetic pathway. This suggests a bio-inspired or ""collective synthesis"", as has been devised by D: W. MacMillan. However, a biosynthetic pathway is confined to these structure elements, thus limiting synthesis with regard to structure diversification. In this research proposal the applicant exemplarily devises a strategic concept to overcome these limitations, by replacing the dogma of ""retrosynthetic analysis"" with ""structure pattern recognition"". This concept is termed ""Artificial Natural Product Systems Synthesis — ANaPSyS"", and aims to supersede the current ""logic of chemical synthesis"" as a standard practice in this field.
ANaPSyS exclusively categorizes natural products based on structural relationships — regardless of biogenetic origin. The structure pattern analysis groups natural products according to their shared core structure, and thereof creates a common precursor called ""privileged intermediate (PI)"". This intermediate is resembled in each of these natural products and is architecturally less complex. As a result every member of this natural product group can originate from a different natural product family and is obtained via this ""privileged intermediate"", which serves as basis for the artificial synthetic network.
With ANaPSyS a synthetic route is not restricted to a single target structure anymore (as in conventional synthesis). In comparison with bio-inspired synthesis, which is limited to a single natural product family, ANaPSyS enables the synthesis of a whole set of natural product families. With every synthesis accomplished, the network is upgraded — hence diversification leads to a rise in revenue. As a consequence, synthetic efficiency is drastically enhanced, therefore profoundly boosting and facilitating lead structure development.
"
Summary
"Traditionally, natural products are classified into ""natural product families"". Within a family all congeners display specific structure elements, owing to their common biosynthetic pathway. This suggests a bio-inspired or ""collective synthesis"", as has been devised by D: W. MacMillan. However, a biosynthetic pathway is confined to these structure elements, thus limiting synthesis with regard to structure diversification. In this research proposal the applicant exemplarily devises a strategic concept to overcome these limitations, by replacing the dogma of ""retrosynthetic analysis"" with ""structure pattern recognition"". This concept is termed ""Artificial Natural Product Systems Synthesis — ANaPSyS"", and aims to supersede the current ""logic of chemical synthesis"" as a standard practice in this field.
ANaPSyS exclusively categorizes natural products based on structural relationships — regardless of biogenetic origin. The structure pattern analysis groups natural products according to their shared core structure, and thereof creates a common precursor called ""privileged intermediate (PI)"". This intermediate is resembled in each of these natural products and is architecturally less complex. As a result every member of this natural product group can originate from a different natural product family and is obtained via this ""privileged intermediate"", which serves as basis for the artificial synthetic network.
With ANaPSyS a synthetic route is not restricted to a single target structure anymore (as in conventional synthesis). In comparison with bio-inspired synthesis, which is limited to a single natural product family, ANaPSyS enables the synthesis of a whole set of natural product families. With every synthesis accomplished, the network is upgraded — hence diversification leads to a rise in revenue. As a consequence, synthetic efficiency is drastically enhanced, therefore profoundly boosting and facilitating lead structure development.
"
Max ERC Funding
1 497 000 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym ANTIBACTERIALS
Project Natural products and their cellular targets: A multidisciplinary strategy for antibacterial drug discovery
Researcher (PI) Stephan Axel Sieber
Host Institution (HI) TECHNISCHE UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), PE5, ERC-2010-StG_20091028
Summary After decades of successful treatment of bacterial infections with antibiotics, formerly treatable bacteria have developed drug resistance and consequently pose a major threat to public health. To address the urgent need for effective antibacterial drugs we will develop a streamlined chemical-biology platform that facilitates the consolidated identification and structural elucidation of natural products together with their dedicated cellular targets. This innovative concept overcomes several limitations of classical drug discovery processes by a chemical strategy that focuses on a directed isolation, enrichment and identification procedure for certain privileged natural product subclasses. This proposal consists of four specific aims: 1) synthesizing enzyme active site mimetics that capture protein reactive natural products out of complex natural sources, 2) designing natural product based probes to identify their cellular targets by a method called activity based protein profiling , 3) developing a traceless photocrosslinking strategy for the target identification of selected non-reactive natural products, and 4) application of all probes to identify novel enzyme activities linked to viability, resistance and pathogenesis. Moreover, the compounds will be used to monitor the infection process during invasion into eukaryotic cells and will reveal host specific targets that promote and support bacterial pathogenesis. Inhibition of these targets is a novel and so far neglected approach in the treatment of infectious diseases. We anticipate that these studies will provide a powerful pharmacological platform for the development of potent natural product derived antibacterial agents directed toward novel therapeutic targets.
Summary
After decades of successful treatment of bacterial infections with antibiotics, formerly treatable bacteria have developed drug resistance and consequently pose a major threat to public health. To address the urgent need for effective antibacterial drugs we will develop a streamlined chemical-biology platform that facilitates the consolidated identification and structural elucidation of natural products together with their dedicated cellular targets. This innovative concept overcomes several limitations of classical drug discovery processes by a chemical strategy that focuses on a directed isolation, enrichment and identification procedure for certain privileged natural product subclasses. This proposal consists of four specific aims: 1) synthesizing enzyme active site mimetics that capture protein reactive natural products out of complex natural sources, 2) designing natural product based probes to identify their cellular targets by a method called activity based protein profiling , 3) developing a traceless photocrosslinking strategy for the target identification of selected non-reactive natural products, and 4) application of all probes to identify novel enzyme activities linked to viability, resistance and pathogenesis. Moreover, the compounds will be used to monitor the infection process during invasion into eukaryotic cells and will reveal host specific targets that promote and support bacterial pathogenesis. Inhibition of these targets is a novel and so far neglected approach in the treatment of infectious diseases. We anticipate that these studies will provide a powerful pharmacological platform for the development of potent natural product derived antibacterial agents directed toward novel therapeutic targets.
Max ERC Funding
1 500 000 €
Duration
Start date: 2010-11-01, End date: 2015-10-31
Project acronym APPELS
Project A Probe of the Periodic Elements for Life in the Sea
Researcher (PI) Rosalind Emily Mayors Rickaby
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Consolidator Grant (CoG), PE10, ERC-2015-CoG
Summary "Chemical elements are the building blocks of life. The major elements, C, H. O, N, P, S are easily recognised as essential nutrients, but their use by life relies on metalloproteins. The identity of the metal centres of these metalloproteins and even the broader palette of trace elements fundamental to life are remarkably poorly known. Whole genomes remain opaque to decoding of this bioinorganic dimension, and optimal trace element concentrations for physiological function. Defining the elemental requirements for maximum growth rate of photosynthesising phytoplankton in the ocean, is critical to understanding Earth's climate. Although microscopic in stature, phytoplankton exert a gigantic influence on the biological pumping of carbon from the atmosphere to the deep ocean. Yet their metal requirements are poorly constrained, being inferred from cellular quotas and "nutrient-like" ocean metal distributions, susceptible to ambiguity between mistaken cellular uptake and use.
APPELS will undertake a two-pronged approach to define the modern marine metallome/metalloproteome. I will explore the expanse of the periodic table for novel required elements by growing phytoplankton, representative of the broadest chemotypes, in manipulated media, to delineate optimal conditions for growth whereby any limitation at lowered concentrations implies use. The second prong uses cutting-edge techniques that unite methods from proteomics with geochemical mass-spectrometry to allow both metals and their associated proteins to be examined comprehensively. APPELS will transform our understanding of the essential elements in the ocean and how the biological pump of carbon is geared to ocean chemistry in an evolving world. More broadly, APPELS will provide a step change in documented protein-metal binding centres, with implications for discovery of novel biochemical pathways, and optimal nutrition."
Summary
"Chemical elements are the building blocks of life. The major elements, C, H. O, N, P, S are easily recognised as essential nutrients, but their use by life relies on metalloproteins. The identity of the metal centres of these metalloproteins and even the broader palette of trace elements fundamental to life are remarkably poorly known. Whole genomes remain opaque to decoding of this bioinorganic dimension, and optimal trace element concentrations for physiological function. Defining the elemental requirements for maximum growth rate of photosynthesising phytoplankton in the ocean, is critical to understanding Earth's climate. Although microscopic in stature, phytoplankton exert a gigantic influence on the biological pumping of carbon from the atmosphere to the deep ocean. Yet their metal requirements are poorly constrained, being inferred from cellular quotas and "nutrient-like" ocean metal distributions, susceptible to ambiguity between mistaken cellular uptake and use.
APPELS will undertake a two-pronged approach to define the modern marine metallome/metalloproteome. I will explore the expanse of the periodic table for novel required elements by growing phytoplankton, representative of the broadest chemotypes, in manipulated media, to delineate optimal conditions for growth whereby any limitation at lowered concentrations implies use. The second prong uses cutting-edge techniques that unite methods from proteomics with geochemical mass-spectrometry to allow both metals and their associated proteins to be examined comprehensively. APPELS will transform our understanding of the essential elements in the ocean and how the biological pump of carbon is geared to ocean chemistry in an evolving world. More broadly, APPELS will provide a step change in documented protein-metal binding centres, with implications for discovery of novel biochemical pathways, and optimal nutrition."
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym ARTISYM
Project Artificial endosymbiosis
Researcher (PI) Jan Van hest
Host Institution (HI) TECHNISCHE UNIVERSITEIT EINDHOVEN
Call Details Advanced Grant (AdG), PE5, ERC-2015-AdG
Summary Living organisms have acquired new functionalities by uptake and integration of species to create symbiotic life-forms. This process of endosymbiosis has intrigued scientists over the years, albeit mostly from an evolution biology perspective. With the advance of chemical and synthetic biology, our ability to create molecular-life-like systems has increased tremendously, which enables us to build cell and organelle-like structures. However, these advances have not been taken to a level to study comprehensively if endosymbiosis can be applied to non-living systems or to integrate living with non-living matter. The aim of the research described in the ARTISYM proposal is to establish the field of artificial endosymbiosis. Two lines of research will be followed. First, we will incorporate artificial organelles in living cells to design hybrid cells with acquired functionality. This investigation is scientifically of great interest, as it will show us how to introduce novel compartmentalized pathways into living organisms. It also serves an important societal goal, as with these compartments dysfunctional cellular processes can be corrected. We will follow both a transient and a permanent approach. With the transient route biodegradable nanoreactors are introduced to supply living cells temporarily with novel function. Functionality is permanently introduced using genetic engineering to express protein-based nanoreactors in living cells, or via organelle transplantation of healthy mitochondria in diseased living cells. Secondly I aim to create artificial cells with the ability to perform endosymbiosis; the uptake and presence of artificial organelles in synthetic vesicles allows them to dynamically respond to their environment. Responses that are envisaged are shape changes, motility, and growth and division. Furthermore, the incorporation of natural organelles in liposomes provides biocatalytic cascades with the necessary cofactors to function in an artificial cell
Summary
Living organisms have acquired new functionalities by uptake and integration of species to create symbiotic life-forms. This process of endosymbiosis has intrigued scientists over the years, albeit mostly from an evolution biology perspective. With the advance of chemical and synthetic biology, our ability to create molecular-life-like systems has increased tremendously, which enables us to build cell and organelle-like structures. However, these advances have not been taken to a level to study comprehensively if endosymbiosis can be applied to non-living systems or to integrate living with non-living matter. The aim of the research described in the ARTISYM proposal is to establish the field of artificial endosymbiosis. Two lines of research will be followed. First, we will incorporate artificial organelles in living cells to design hybrid cells with acquired functionality. This investigation is scientifically of great interest, as it will show us how to introduce novel compartmentalized pathways into living organisms. It also serves an important societal goal, as with these compartments dysfunctional cellular processes can be corrected. We will follow both a transient and a permanent approach. With the transient route biodegradable nanoreactors are introduced to supply living cells temporarily with novel function. Functionality is permanently introduced using genetic engineering to express protein-based nanoreactors in living cells, or via organelle transplantation of healthy mitochondria in diseased living cells. Secondly I aim to create artificial cells with the ability to perform endosymbiosis; the uptake and presence of artificial organelles in synthetic vesicles allows them to dynamically respond to their environment. Responses that are envisaged are shape changes, motility, and growth and division. Furthermore, the incorporation of natural organelles in liposomes provides biocatalytic cascades with the necessary cofactors to function in an artificial cell
Max ERC Funding
2 500 000 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
