Project: Design, synthesis and lead generation of novel siderophore conjugates for the detection and treatment of infections by Gram-negative pathogens

Acronym SCAN (Reference Number: JPIAMR_2018_P009)
Duration 01/01/2019 - 31/12/2021
Project Topic There is a strong need for novel, innovative therapeutic solutions for infections caused by Gramnegative pathogens. In addition, there is a lack of tools to diagnose bacterial infections at deep body sites, e.g. on implant surfaces. In the project SCAN (Siderophore Conjugates Against Gram-Negatives), we apply a rational design approach to establish a targeting conjugate platform that can be used to both diagnose as well as treat bacterial infections (‘theranostics’ principle). The conjugates are actively transported into bacteria through their iron transport machinery that accepts siderophores as substrates. This concept has recently been validated clinically and addresses a key issue of Gramnegative pathogens, the impaired translocation into the cell. We will design and synthesise novel siderophores that employ novel central scaffolds and combinations of iron-binding motifs. Those will be coupled with hitherto unexplored effectors: RNA polymerase inhibitors are employed as potent antibiotics, and dioxetane-based chemiluminescent probes will be used for imaging. As a linkage between siderophore and antibiotic, cleavable, self-immolative linkers (e.g. trimethyl lock) will be constructed. The conjugates will be characterised in cellular assays and in infection models in mice. Their translocation and resistance mechanisms will be investigated by genetic and proteomic methods. The project should yield novel antibiotic lead structures with proven efficacy in vivo.
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Project partner

Number Name Role Country
1 Helmholtz Centre for Infection Research Coordinator Germany
2 Tel-Aviv University Partner Israel
3 CNRS - Université de Strasbourg Partner France