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Sweet Theranostics in Bitter Infections - Seek and Destroy

Periodic Reporting for period 2 - SWEETBULLETS (Sweet Theranostics in Bitter Infections - Seek and Destroy)

Reporting period: 2018-08-01 to 2020-01-31

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, my team and 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.
We will establish Sweet Imaging: Design & conjugation of lectin-directed ligands to imaging probes, Optimization of ligand/linker, in vivo proof-of-concept imaging study.
Furthermore, we will establish Sweet Targeting: Delivery of antibiotics to the infection through covalent linking of lectin directing 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.
In a last work package we aim to develop 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.
My team and I at HZI have embarked on a systematic evaluation of lectin directing probes, linker types and imaging agents as well as antibiotic cargo. The successful proof of concept of the imaging of Pseudomonas biofilms has been provided and was published in the manuscript: Wagner, S.; Hauck, D.; Hoffmann, M.; Sommer, R.; Joachim, I.; Müller, R.; Imberty, A.; Varrot, A.; Titz, A.* Covalent lectin inhibition and its application in bacterial biofilm imaging. Angew. Chem. Int. Ed. Engl. 2017, 56, 16559-16564. A large set of follow-up imaging agents has been prepared and tested in in vitro biofilm assays.
Furthermore, we have explored the structure activity relationship of LecB directed group. In the context of sweet targeting antibiotics, we prepared a large set of conjugates and analysed the relatively steep SAR of various linkers and lectin-directing groups on antimicrobial activity. Nanocarriers with lectin-directing groups have been prepared and are currently being studied in a number of assays.
The first lectin-directed imaging and targeting probes have been prepared. Proof-of-concept for biofilm imaging has been provided in vitro and the aim for the full project is a successful application in in vivo infection imaging. Furthermore, the conjugates of small molecules and of nano carrier systems show promising properties at the current stage and will be developed further into infection targeting agents that aim to break the resistance barrier.