University of Hannover

Sophisticated signalling systems enable bacteria to occupy almost every single niche on our planet. In such systems, second messengers are crucial information carriers that elicit cellular adaptation to diverse signals. Current dynamics in signalling research have led to the discovery of an exquisite collection of nucleotides that bacteria use as second messengers, including cyclic dimeric adenosine monophosphate (c-di-AMP). A unique feature of c-di-AMP is its essentiality, making it an attractive target for antibiotics. The main objective of this proposal is to uncover the full repertoire of c-di-AMP functions and metabolism in bacteria by using Streptomyces as a model. Streptomyces are our most prolific antibiotic producers and represent an excellent system to study multicellular differentiation. They live in soil, where they encounter diverse environmental cues that trigger antibiotic production and a complex transition from multicellular filaments to spores. c-di-AMP enables Streptomyces to survive osmotic stress caused by rainfall and drought, but interferes with development. How c-di-AMP affects differentiation and how these bacteria adapt to stress signalled by c-di-AMP is unknown. Here, we propose that bacteria use a novel transmembrane signalling pathway to remodel their cell wall for surviving stress mediated by c-di-AMP. We will challenge the current view in the field by showing that the set of enzymes involved in c-di-AMP dynamics is larger than it is currently believed and we will identify new c-di-AMP effectors. Finally, we will explore the potential of c-di-AMP for manipulation of natural product biosynthesis and address the function of a linear di-AMP molecule that is new to signalling research. Our proposed research will not only lead to the discovery of fundamental new principles in bacterial signalling and differentiation but might also identify new cell wall associated targets for drug design and tools for triggering antibiotic biosynthesis.

The synthesis of complex natural products has shaped the field of organic chemistry, with translational applications spreading further into medicinal, agrochemical, and material sciences. As the largest class of natural products, terpenoids play a variety of roles in mediating antagonistic and beneficial interactions macroscopically, i.e., among organisms, and microscopically, i.e., on a (sub)cellular level. They defend many species of plants, animals, and microorganisms against predators, pathogens, and competitors, and they are involved in conveying messages within these organisms. Facilitating and streamlining the access to the most complex terpenoids, heavily rearranged and highly oxidized triterpenoids, requires an understanding of Nature’s ways to biosynthesize these structures, i.e., of their biogenesis. Biomimetic synthesis can only then provide routes which outrival classical retrosynthetic planning. In the absence of a plausible biogenesis proposal, this strategy is not accessible, though. So far, biogenesis proposals have, in lieu of validated intermediates and enzymes, followed the paradigm of polar mechanisms and evoked standard textbook reactions involving ionic intermediates to account for skeletal rearrangements. The aim of this project is to disprove this paradigm and cross this perceived limit of reactivity. Thus, we will here provide chemical proof that terpenoid biogenesis is not sufficiently explained by polar mechanisms, but rather is an intricate interplay of radical and polar reactivity. The border we attempt to cross is the one between two very different chemical entities: radicals and ions. Development of radical-polar crossover logic will evolve robust and selective routes to access drugable triterpenoid natural products modulating the immune system, targeting cancer, and combating pathogens. Added value comes from the involvement of modern photoredox catalysis strategies to initiate radical-polar crossover cascades in sustainable fashion.

With explosive development and demand of implantable bio-applications, battery replacement becomes a key issue to achieve permanent implantation in vivo. Recent advances in energy nanogenerators have allowed for self-power function by conversing mechanical energy to electric energy, promising the battery-free implantation of bio-applications. Among the emerging nano harvesting technologies, triboelectrification initially proposed in 2012 is the front one due to universal availability, from enormous to tiny movements and even low-frequency motion in vivo. Another advantage of triboelectrification is the abundant choices of materials to meet the requirement of biocompatibility. Hence, the triboelectrification is the enabling technology for the next generation self-powered implant. Recently, researchers have commenced implanting triboelectric nanogenerators (TENG) in animals to evaluate the potential of energy harvesting from heart beating and respiration. However, the understanding of interactions between triboelectrification and muscle dynamics for energy harvesting is unclear. The experiments are limited in measuring, explaining and quantifying the performance of TENG by ignoring the complex dynamics of muscles, significantly hindering the application of TENG as implantable device. The proposal aims to develop a triboelectrification-muscle dynamics (TEMD) framework based on experiment and modelling to support the design, characterization and optimization of TENG for implantable bio-applications under different muscle dynamics on macro/nano scales. The framework will be able to (1) predict the output performance of TENG at any position of specific muscle, and (2) to design and optimize TENG in certain circumstances for the improvement of performance and durability. Such framework will also provide solid foundations and physical-mechanical guidance for other implantable energy harvesters, such as piezoelectric and flexoelectric nanogenerators.

Aerogels and hydrogels from nanocrystal building blocks are a fascinating novel class of materials with extremely low densities and large specific surfaces, which partially exhibit the advantageous properties of their nanoscopic building blocks (e.g. size quantized fluorescence or catalytic activity). In the present project, multicomponent gels with controlled mechanical properties, plasmon enhanced fluorescence, photocatalytic properties, and with controlled conductivity properties will be synthesized. These new materials will not only exhibit the nanoscopic properties of their building blocks, but they will also exhibit new properties which are neither accessible from nanoparticle nor from bulk material. This will e.g. be achieved due to nanoscopic interactions between the materials or due to synergistic combination effects caused by appropriate material combination. Synthetic routes for nanostructuring, microstructuring and macrostructuring nanocrystal hydrogels and aerogels will be developed. Nanostructuring involves advancement of colloidal nanocrystal synthesis as well as postsynthetic gel modifications. Microstructuring involves synthesizing multicomponent gels with defined contact points of the materials and intercalating multicomponent gels. Macrostructuring involves implementation of the gelation techniques into 3D printing, and gel deformation by external triggers and will enhance the applicability of gels. The materials developed will be tailored for several physicochemical effects and hence applications. While the project focuses on the synthesis of these new materials with defined physicochemical properties, the outcome of this project will influence many different research and application fields, such as electrodes and batteries, sensors, photocatalysis and catalysis, solar cells, air and solar batteries, and even membranes and touch screen devices.