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HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH
|Coordinator Country||Germany [DE]|
|Total cost||1˙499˙551 €|
|EC max contribution||1˙499˙551 € (100%)|
1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
|Duration (year-month-day)||from 2017-02-01 to 2022-01-31|
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|1||HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH||DE (BRAUNSCHWEIG)||coordinator||1˙499˙551.00|
Bacterial infections are now a global threat demanding novel treatments due to the appearance of resistances against antibiotics at a high pace. The ESKAPE pathogens are those with highest importance in the EU and chronic infections due to biofilm formation are a particular task. Noninvasive pathogen-specific imaging of the infected tissue is not clinically available. Its successful implementation will enable the choice of appropriate therapy and boost efficacy. Furthermore, Gram-negative bacteria have a highly protective cellular envelope as an important resistance mechanism for drugs acting intracellularly, resulting in an alarmingly empty drug-pipeline. To overcome this gap, I will establish Lectin-directed Theranostics targeting pathogens via their extracellular carbohydrate-binding proteins at the site of infection for specific imaging and treatment. This will be implemented for the highly resistant ESKAPE pathogen Pseudomonas aeruginosa through 3 different work packages. WP1 Sweet Imaging: Design & conjugation of lectin-directed ligands to imaging probes, Optimization of ligand/linker, in vivo proof-of-concept imaging study. WP2 Sweet Targeting: Delivery of antibiotics to the infection through covalent linking of lectindirecting groups. Employing different antibiotics, assessment of bactericidal potency and targeting efficiency. Manufacturing of nano-carriers with surface exposed lectin-directed ligands, noncovalent charging with antibiotics. In vitro and in vivo targeting. WP3 Sweet SMART Targeting: Conjugates as SMART drugs: specific release of anti-biofilm lectin inhibitor and drug cargo upon contact with pathogen, development of linkers cleavable by pathogenic enzymes. SWEETBULLETS will establish fundamentally novel lectin-directed theranostics to fight these deleterious infections and provide relief to nosocomially infected and cystic fibrosis patients. It is rapidly extendable towards other ESKAPE pathogens, e.g. Klebsiella spp..
|year||authors and title||journal||last update|
Roman Sommer, Katharina Rox, Stefanie Wagner, Dirk Hauck, Sarah S. Henrikus, Shelby Newsad, Tatjana Arnold, Thomas Ryckmans, Mark BrÃ¶nstrup, Anne Imberty, Annabelle Varrot, Rolf W. Hartmann, Alexander Titz
Anti-biofilm Agents against Pseudomonas aeruginosa : A Structureâ€“Activity Relationship Study of C -Glycosidic LecB Inhibitors
published pages: 9201-9216, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.9b01120
|Journal of Medicinal Chemistry 62/20||2020-04-24|
Stefanie Wagner, Dirk Hauck, Michael Hoffmann, Roman Sommer, Ines Joachim, Rolf MÃ¼ller, Anne Imberty, Annabelle Varrot, Alexander Titz
Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging
published pages: 16559-16564, ISSN: 1433-7851, DOI: 10.1002/anie.201709368
|Angewandte Chemie International Edition 56/52||2019-04-03|
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