Tracking Uptake and Metabolism of Xenometallomycins Using a Multi-Isotope Tagging Strategy
Year: 2022
Type: article
Abstract: Synthetic and naturally occurring siderophores and their conjugates provide access to the bacterial cytoplasm via active membrane transport. Previously, we displaced iron with the radioactive isotope 67 Ga to quantify and track in vitro and in vivo uptake and distribution of siderophore Trojan Horse antibiotic conjugates. Here, we introduce a multi-isotope tagging strategy to individually elucidate the fate of metal cargo and the ligand construct with radioisotopes 67 Ga and 124 I. We synthesized gallium(III) model complexes of a ciprofloxacin-functionalized linear desferrichrome (Ga- D6 ) and deferoxamine (Ga- D7 ) incorporating an iodo-tyrosine linker to enable radiolabeling using the metal-binding ( 67 Ga) and the cargo-conjugation site ( 124 I). Radiochemical experiments with Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa wt strains show that 67 Ga- D6 / D7 and Ga- D6 - 124 I/ D7 - 124 I have comparable uptake, indicating intact complex import and siderophore-mediated uptake. In naive mice, 67 Ga- D6 / D7 and Ga- D6 - 124 I/ D7 - 124 I demonstrate predominantly renal clearance; urine metabolite analysis indicates in vivo dissociation of Ga(III) is a likely mechanism of degradation for 67 Ga- D6 / D7 when compared to ligand radiolabeled compounds, Ga- D6 - 124 I/ D7 - 124 I, which remain >60% intact in urine. Cumulatively, this work demonstrates that a multi-isotope tagging strategy effectively elucidates the in vitro uptake, pharmacokinetics, and in vivo stability of xenometallomycins with modular chemical structures.
Source: ACS Infectious Diseases
Authors: Apurva Pandey, Minhua Cao, Eszter Boros
Institution: Stony Brook University
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G3023813853, G7079796644
OpenAlex ID: W4220747342