Researchers at Los Alamos National Laboratory have developed a promising new approach for diagnosing and treating drug-resistant pathogenic microorganisms that uses bacteria-specific siderophores to convey a treatment molecule directly to a pathogen. Siderophores are “iron carriers,” which are molecules produced by microorganisms such as fungi and bacteria that transport iron across cell membranes.
The work done by Los Alamos and University of California-Berkeley scientists shows that if the right radioisotope can be attached to the right siderophore, it can be very effective in selectively locating a pathogenic cell, entering the cell, and destroying it with radioactive alpha particles.
This research, recently published in the chemistry journal Dalton Transactions, used the pathogen Staphylococcus aureus (S. aureus), the bacteria that causes methicillin-resistant S. aureus (MRSA) infections.
The MRSA cells were targeted with a siderophore in which the iron had been swapped for thorium-232—a surrogate for therapeutic alpha-emitting thorium-227—to enable macroscopic physiochemical characterization. The siderophore is very specific to the MRSA bacteria, which uses it to acquire vital nutrients, namely iron. Because it is so selective, the siderophore can function as a “smart” delivery vehicle for the therapeutic thorium, ensuring that it destroys the pathogen without unduly damaging surrounding tissues. Similar approaches have been used for alpha-therapeutic fungal therapies and radioimaging of bacterial infections.
Using nuclear magnetic resonance, infrared and Raman spectroscopies, the team examined the structure of the thorium complex. A key additional step was a fluorescent reporter to the siderophore such that they could image the complex within cultures of Staphylococcus aureus.
The results suggest that the thorium-bound siderophore can be used to target the pathogen and lay the groundwork for native, siderophore-based targeted alpha therapeutics. Siderophore uptake is a necessary process for pathogen survival, making the evolution of resistance mechanisms unlikely. Next steps will include a broader demonstration with other siderophores and their corresponding host bacteria.
This research was supported by Los Alamos National Laboratory’s Laboratory Directed Research and Development Office and the U.S. DOE Isotope Program, managed by the Office of Science for Nuclear Physics. Additional funding from the Office of Science, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences, and Biosciences, Heavy Element Chemistry Program of the U.S. Department of Energy.
Paper reference: “ThIV–Desferrioxamine: Characterization of a Fluorescent Bacterial Probe.” K. Alrich, M. Livshits, L. Stromberg, M. T. Janicke, M. Nhu Lam, B. W. Stein, G. Wagner, R. Abergel, H. Mukundan, S. A. Kozimor and L. M. Lilley, Dalton Trans., 2021, DOI: 10.1039/D1DT02177J.