Bacteria assimilate physiologically essential iron by utilizing high affinity ferric ion chelators, siderophores that are internalization by siderophore-specific bacterial transmembrane proteins. Ga3+ is an ideal, non-redox active mimic of Fe3+, and thus has high affinity to Fe3+-siderophores We hypothesize that Ga-siderophores linked with antibiotics can take advantage of the active siderophore internalization pathway and accumulate in sites of infection with high specificity and starve bacterial populations of Fe3+, effectively exhibiting antibiotic properties. Additionally, the radioactive SPECT isotope 67Ga enables assessment of stability, pharmacokinetics and opens opportunities to non-invasively monitor the time course of bacterial infections, as treatment is employed. We have successfully synthesized two siderophore-drug conjugates (sideromycins) based on desferrichrome (DFC) and desferrioxamine (DFO) scaffolds and showed that Ga-D2, our first generation lead efficiently potentiates the efficacy of ciprofloxacin, while the radiolabeled version 67Ga-D2 is suitable for in vivo tracking and evaluation of pharmacokinetics. Recently, we tested Ga-D2 in pathogenic, clinical isolate strains with carbapenem resistance. Ga-D2 is especially potent in P. aeruginosa strains and demonstrated efficiency in overcoming gallium- and ciprofloxacin resistance with a MIC90 of 12.5 µM in CRE 237, while ciprofloxacin and gallium salts did not inhibit growth; a wide-ranging activity screen in &gt;100 clinical isolates is underway. Here, we will also present our efforts on establishing structure-activity-relationships (SAR) of second-generation derivatives based on the Ga-D2 lead with respect to activity, selectivity and stability. We will also carry out radiolabeling studies with 67Ga(III) to produce the radiochemical complexes for biodistribution and metabolic stability experiments on naïve CBJ mice.

Gallium based ciprofloxacin siderophore-conjugates with broad spectrum antibiotic activity

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.