Antibiotic resistance is an increasing global health threat and resistance against known antibiotics requires new approaches to antibiotic drug development. Bacterial virulence is closely tied to the uptake of essential nutrients such as trace metal ions; most pathogenic bacteria use endogenous iron chelator molecules, siderophores, to sequester Fe3+ from the host. The bacterial iron dependence provides a convenient route for the development of siderophore-based antibiotic Trojan horse conjugates that explore bacteria’s iron uptake to deliver drugs. Our first-generation gallium siderophore antibiotic conjugates, Ga-D1 and Ga-D5 [1] display promising inhibitory growth activity and indicate that gallium complexation can enhance potency of the corresponding, metal-free apo conjugate [2]. We also employed tracing with 67Ga analogues to study and quantitate bacterial uptake and in vivo metabolism. However, this approach does not allow the tracing and determination of pharmacokinetics of the ligand component of these constructs, especially following dissociation of the radioactive 67Ga ion from the siderophore antibiotic conjugate. In order to address this shortcoming and shed light on the in vitro and in vivo metabolic fate of the siderophore-antibiotic conjugate, we have developed an approach to incorporate a radioactive isotope within both the metal-binding (67Ga) and the drug cargo linker site (124I). We will discuss our results with these dual-labeled constructs including their synthesis, radiochemistry, in vitro bacterial uptake and in vivo metabolite experiments in mice.

Multi-isotope tagging strategy to study uptake and distribution of siderophore-based antibiotic Trojan Horse conjugates

ACS Spring 2022

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