Theranostic Gallium Siderophore Ciprofloxacin Conjugate with Broad Spectrum Antibiotic Potency

Apurva Pandey, Chloé Savino, Shin Hye Ahn, Zhaoyong Yang, Steven G. Van Lanen, Eszter Boros

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)9947-9960
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number21
DOIs
StatePublished - Nov 14 2019

Bibliographical note

Funding Information:
E.B. acknowledges funding sources, specifically the NIH for a Pathway to Independence Award (R00HL125728) and Stony Brook University for startup funds. S.G.V.L is supported by NIH (R01AI087849).

Funding Information:
E.B. acknowledges funding sources, specifically the NIH for a Pathway to Independence Award (R00HL125728) and Stony Brook University for startup funds. S.G.V.L is supported by NIH (R01AI087849).

Publisher Copyright:
Copyright © 2019 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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