Hospital infections and infection-related deaths are caused by a growing number of resistance cases, as reported by the Center for Disease Control (CDC). There is a need for potent therapies which efficiently overcome resistance of pathogenic strains. Ideal biological therapy targets for infection are markers characteristic for bacterial pathogens. Uptake mechanisms of ferric iron sequestration specific to bacterially produced small molecular iron complexes, siderophores, are highly conserved and expressed among Gram-positive and Gram-negative bacterial strains, while completely absent in mammalian hosts. The siderophore-mediated uptake of iron has been exploited successfully to deliver of antibiotics following a “Trojan horse” strategy. Siderophore-antibiotic conjugates can circumvent membrane-permeability associated resistance pathways or specifically target pathogenic strains with upregulated siderophore-degrading enzymes in the bacterial cytoplasm; however, broad spectrum antibiotic activity remains elusive. Hexadentate siderophores exhibit exceptionally high affinity for both Fe3+ and the non-redox active, iron mimetic Ga3+ (KD &gt; 10-27 M). Our lab has successfully developed a gallium(III)-containing siderophore-antibiotic (ciprofloxacin) conjugate, Ga-D2, that exhibits broad spectrum activity in ESKAPE pathogens and efficiently overcomes resistance in carbapenem and ciprofloxacin-resistant, clinical isolates of P. aeruginosa in vitro. We show that synthesis of the corresponding Ga-67 radiolabeled tracer analogue, 67Ga-D2 enables characterization of bacterial uptake in vitro, as well as the in vivo pharmacokinetics and stability of Ga-D2. We demonstrate that drug development in medicinal inorganic chemistry can be significantly aided by the synthesis, in vitro and in vivo assessment of the radiotracer analogues. The comprehensive information obtained with our first-generation lead Ga-D2 guides our currently ongoing, second generation drug and tracer design.

Developing metallomycins as broad spectrum active antibiotics: Medicinal inorganic, radiochemistry-aided approach

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.