Info
Talk Summary:
Work by us and others (Decristoforo, Brönstrup) has provided evidence that versatile iron-binding bacterial natural products, termed siderophores, are a versatile platform for the selective imaging and molecular interrogation of bacterial pathogens in vivo. Building on the natural iron acquisition pathways exploited by bacteria, we developed radiolabeled siderophore conjugates that are actively transported into bacterial cells through high-affinity outer membrane transport systems. These agents enable highly specific positron emission tomography (PET) imaging of bacterial infections while minimizing uptake in sterile inflammation and healthy tissues, addressing a longstanding challenge in infection imaging.
A central advance of this work was the demonstration that synthetic siderophore scaffolds can be engineered not only to preserve transporter recognition but also to incorporate functional cargo without compromising bacterial uptake. Through systematic structure-activity studies, we identified molecular features governing transporter engagement and showed that these principles can be leveraged to design imaging probes with broad applicability across clinically important bacterial species.
More recently, we expanded this platform by introducing covalent cross-linking functionality into siderophore transport ligands. These probes selectively bind and irreversibly capture TonB-dependent siderophore transporters upon recognition, enabling direct identification and characterization of bacterial uptake proteins in their native cellular environment. This strategy provides a powerful chemical biology tool to study transporter selectivity, expression, and dynamics while overcoming limitations associated with transient ligand-receptor interactions.
The combination of molecular imaging and covalent target engagement establishes a unified platform for studying bacterial nutrient acquisition in vivo. The imaging agents provide noninvasive assessment of bacterial burden and transporter activity within the host, whereas the cross-linking probes enable mechanistic investigation of the transport machinery responsible for probe uptake in vitro.
In this talk, I will discuss how we harness these complementary technologies to identify pathogen-specific biomarkers, characterize transporter expression across bacterial species, and inform the rational design of next-generation targeted diagnostics and therapeutics for infection.
Presenter Biography:
The Boros lab operates at the interface of inorganic chemistry, molecular imaging, radiopharmaceutical science, and chemical biology. We develop next-generation molecular platforms for the targeted diagnosis and treatment of disease, with a particular emphasis on bacterial infections and cancer. Research spans from the use of luminescent lanthanide coordination complexes as in vivo optical imaging tools, to the development of multi-isotope compatible radiolabeling platform technologies for FAP and PSMA radiopharmaceuticals, to establishing probes to study bacterial metal homeostasis in vitro and in vivo using non-invasive nuclear imaging.
Author
Eszter Boros
University of Wisconsin-Madison