Bacteria assimilate physiologically essential iron by utilizing high affinity ferric ion chelators, siderophores that are internalization by siderophore-specific bacterial transmembrane proteins. The xenometal 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 three siderophore-drug conjugates (sideromycins) based on desferrichrome (LDFC) scaffold 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 have developed and extensively tested Ga-D5, a second-generation conjugate with a cleavable serine linker in wild type bacterial strains. Our experiments revealed that Ga-D5 is exceptionally active against S.aureus strains with a MIC90 of 0.093 µM, exceeding the potency of the parent antibiotic by an order of magnitude. Biodistribution of 67Ga-D5 in naïve mice and in a mouse model of intramuscular infection revealed renal clearance and enhanced uptake in infected tissues when compared to 67Ga-citrate, motivating assessment of the compound’s potential as an intravenously administered antibiotic for the treatment of Gram-positive infection. Corresponding results will be presented, as well as the activity of 67Ga-D5 against methicillin resistant S.aureus (MRSA) strains.

Gallium based ciprofloxacin siderophore-conjugate with high activity against S.aureus

ACS Fall 2021

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