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CISPA

Helmholtz Center for Information Security
Country: Germany
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89 Projects, page 1 of 18
  • Funder: EC Project Code: 101103471
    Funder Contribution: 173,847 EUR

    Due to the current antimicrobial resistance crisis, addressing underexplored targets to afford anti-infective compounds with novel modes of action is urgently needed. Antimicrobial resistance not only poses a threat to public health, but is a substantial cost burden on the healthcare system. This proposal focuses on the design and synthesis of novel inhibitors of the target 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase (IspE). IspE catalyzes the fourth step in the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway which is essential for medically relevant pathogens (e.g., Enterobacter coli, Klebsiella pneumoniae, Mycobacterium tuberculosis and Pseudomonas aeruginosa) but entirely absent in humans, making this enzyme a promising drug target. We will initially explore drug fragments through the screening of carefully constructed fragment libraries, followed by hit-to-lead optimization for promising compounds. Target confirmation will be performed using a biologically active small-molecule photo-crosslinking probe and a crystal structure of IspE obtained in complex with a promising inhibitor. The investigation of potential for therapeutic intervention via inhibition of IspE will result in several potent inhibitors, enhancing the knowledge of this underexplored enzyme target and opening up access for further exploration of potent inhibitors. This research will greatly contribute to the discovery of novel anti-infective agents, leading to decreased morbidity and mortality in patients, economical benefits for the health care system in the European Union as well as globally.

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  • Funder: EC Project Code: 793858
    Overall Budget: 159,461 EURFunder Contribution: 159,461 EUR

    T cell memory is the cornerstone of protective immunity and the key determinant of the efficacy of vaccination approaches. Memory inflation (MI) is a unique type of CD8+ T cell memory characterized by the induction of robust and durable populations of functional effector/effector memory CD8+ T cells that is elicited by latently persistent cytomegalovirus (CMV) infections. Accumulating evidence argues that inflationary T cells can provide exceptionally strong immune protection. Hence, several translational approaches involving MI, such as CMV vector-based vaccines, are subject of ongoing pre-clinical and clinical projects. Despite this, little is known about the cellular and molecular mechanisms governing the induction and maintenance of MI. In this proposal, I aim to identify and characterize the latently infected cell type/-s, which sustain CMV-specific inflationary CD8+ T-cells. To this end, I will combine state-of-the-art stromal cell characterization and isolation techniques with generation of novel recombinant virus-based in vivo models enabling (1) tracking of latently infected cells, (2) conditional ablation of viral peptide processing in selected cell types. The results of this action are expected to improve our understanding of the mechanisms and requirements for MI, laying the basis for the development of improved vaccination strategies. Furthermore, identification of the sites of CMV latency in vivo will have implications for development of future clinical strategies aimed at harnessing the ability of CMV to reactivate in immune suppressed patients. Thus, this proposal explores a basic biological question of broad general interest, but also has robust translational potential for applications in human medicine.

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  • Funder: EC Project Code: 334030
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  • Funder: EC Project Code: 101024631
    Overall Budget: 174,806 EURFunder Contribution: 174,806 EUR

    Pseudomonas aeruginosa (PA) is ubiquitous gram-negative bacteria. PA is a serious threat and is considered as a critical priority for treatment development by various institutions such as the World Health Organization. PA can cause infections on various location such as eyes, lung, skin (wounds). Immunocompromised patients are especially at risk, as PA is also able to colonize domestic and hospital fixtures. To add insult to injury, the infection is hard to treat and the number of antibiotic resistant PA is on the rise. The major challenge opposed by PA is its biofilm. Biofilms are a structured bacterial community embedded in a matrix composed of exopolysaccharides, proteins, extracellular DNA, and lipids. PA present in the biofilm are a thousand times less sensitive to antibiotics than their planktonic form. The MONAGEL project propose to fight the PA in the biofilm by developing a hydrogel made of cross-linked lipid nanoparticles. The lipophilic core of the lipid nanoparticles will be used to encapsulate hydrophobic active ingredients, the aqueous cavities of the gel will be used to encapsulate hydrophilic ones. The hydrophobic and hydrophilic compartment will enable work with a broad variety of molecules such as fluorescent probes (which will permit a thorough characterisation of the gel) or active ingredients such as antibiotics and pathoblockers. The latter molecule will be efficient to design the gel towards fighting PA biofilm either by inhibiting quorum sensing (bacterial communication) or lectin interaction (key role in biofilm formation). Well thought work and contingency plans have been put in place to ensure the success of MONAGEL development. The innocuity of the system will be assessed on various cell lines, and the antibiofilm efficacy will be tested on in vitro models. In the end, the MONAGEL efficacy will be demonstrated on a co-culture model (epithelium + biofilm) as a proof-of-concept to serve as a selling point for further development.

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  • Funder: EC Project Code: 281623
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