https://scanproject-siderophore.com/app/uploads/2023/09/logo-scan@2x.png

scan

Design, Synthesis and Lead Generation of Novel Siderophore Conjugates for the Detection and Treatment of Infections by Gram-Negative Pathogens

About the scan project

Among the challenges of modern medicine is the discovery of new antimicrobials to combat multi-drug resistant pathogens. The situation is more dramatic for Gram-negative bacteria because the outer membrane acts as a very efficient permeability barrier against antimicrobials. One of the bottlenecks in antibiotic development is the ability of the drugs to enter bacteria. Consequently, there is strong need for novel and innovative strategies that overcome the outer membrane permeability as well as tools to diagnose bacterial infections at deep body sites, e.g. on implant surfaces, and these are the two challenges of the SCAN (Siderophore Conjugates Against gram-Negatives) project.

The project is funded by JPI-AMR and involves three partners, each brings a unique and complementary expertise to the project.

Discover the project

Vectorization of antibiotics by siderophores

In order to access iron an essential nutrient, bacteria produce siderophores, small molecules able to scavenge iron in the bacterial environment and transport it into bacterial cells. Ferric-siderophore uptake pathways can be considered as gates for the uptake of antibiotics into bacteria. Antibiotics are covalently linked to siderophores and transported with iron into bacteria in a Trojan Horse strategy.

Brönstrup team

The Chemical Biology group of Prof. Dr. Mark Brönstrup at the HZI has gained knowledge on the design and synthesis of new siderophore core structures and their conjugation. The group has all medicinal chemistry expertise in order to optimize conjugates for their use as antibiotic drugs. The PK/PD unit of the HZI, their imaging facility and animal facility enable to validate the novel conjugates in an in vivo context.

Discover the team
Photo credit: Vaincre la Mucoviscidose
Photo credit: Vaincre la Mucoviscidose

Schalk team

The group of Isabelle Schalk (CNRS-University of Strasbourg, France) brings to this project, its longstanding expertise in the investigation of the molecular mechanisms involved in iron homeostasis in Pseudomonas aeruginosa. The group has established a battery of assays to study the mechanims of iron uptake by siderophores into bacteria and has a large collection of mutants of the different iron uptake pathways of P. aeruginosa, involving as well strains expressing fluorescent tagged proteins of the different iron uptake pathways.

Discover the team

Shabat team

Doron Shabat from Tel-Aviv University is an expert in the design and synthesis of chemical probes, their activation mechanisms and their cross-talk to other functional moieties. This group has recently developed new phenoxy-dioxetane chemiluminescent probes with significantly improved chemiluminescense quantum yield under physiological conditions, thereby enabling multiple novel applications in life sciences. This group will contribute specific expertise in dioxetane chemistry and in establishing a specific activation mechanism triggered upon bacterial internalization.

Discover the team
Photo credit: Vaincre la Mucoviscidose

Funding

This project is funded by JPI-AMR.