TY - JOUR
T1 - Theranostic Gallium Siderophore Ciprofloxacin Conjugate with Broad Spectrum Antibiotic Potency
AU - Pandey, Apurva
AU - Savino, Chloé
AU - Ahn, Shin Hye
AU - Yang, Zhaoyong
AU - Van Lanen, Steven G.
AU - Boros, Eszter
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/11/14
Y1 - 2019/11/14
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.9b01388
DO - 10.1021/acs.jmedchem.9b01388
M3 - Article
C2 - 31580658
AN - SCOPUS:85073835949
SN - 0022-2623
VL - 62
SP - 9947
EP - 9960
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -