Theranostic Gallium Siderophore Ciprofloxacin Conjugate with Broad Spectrum Antibiotic Potency

Pathogenic
bacteria scavenge ferric iron from the host for survival
and proliferation using small-molecular chelators, siderophores. Here,
we introduce and assess the gallium­(III) complex of ciprofloxacin-functionalized
desferrichrome (D2) as a potential therapeutic for bacterial
infection using an in vitro assay and radiochemical, tracer-based
approach. Ga-D2 exhibits a minimum inhibitory concentration
of 0.23 μM in Escherichia coli, in line with the parent fluoroquinolone antibiotic. Competitive
and mutant strain assays show that Ga-D2 relies on FhuA-mediated transport for internalization. Ga-D2 is potent against Pseudomonas aeruginosa (3.8 μM), Staphylococcus aureus (0.94 μM), and Klebsiella pneumoniae (12.5 μM), while Fe-D2 is inactive in these strains.
Radiochemical experiments with E. coli reveal that 67Ga-D2 is taken up more efficiently
than 67Ga-citrate. In naive mice, 67Ga-D2 clears renally and is excreted 13% intact in the urine.
These pharmacokinetic and bacterial growth inhibitory properties qualify
Ga-D2 for future investigations as a diagnosis and treatment
tool for infection.