Chemoenzymatic Radiosynthesis of a Gluconate Transporter-Targeted In Vivo Bacterial Sensor From Clinical [¹⁸F]FDG

Many bacteria, but not mammalian cells, can directly import and metabolize extracellular gluconate via gluconate permease (GntP) and kinase (GntK). We hypothesized that fluorine-18 labeled gluconic acid ([¹⁸F]FGA) could leverage unique bacterial gluconate metabolism for pathogen-specific PET imaging. Here, we report [¹⁸F]FGA as a new PET tracer targeting bacterial gluconate metabolism. The chemoenzymatic radiosynthesis of [¹⁸F]FGA was simple, only requiring readily available [¹⁸F]FDG and glucose oxidase. [¹⁸F]FGA showed broad detection sensitivity across multiple bacterial species, including multidrug-resistant clinical isolates. Staphylococcus aureus transposon mutant studies showed substantial loss of [¹⁸F]FGA uptake in GntP and GntK mutants, supporting high specificity for bacterial gluconate metabolism. [¹⁸F]FGA PET selectively highlighted live bacterial infection, with high target-to-nontarget ratios in S. aureus (36-fold) and Escherichia coli (30-fold) in a murine model of myositis. Unlike [¹⁸F]FDG, no appreciable uptake of [¹⁸F]FGA was detected at sites of sterile inflammation. In a Klebsiella pneumoniae pneumonia model, [¹⁸F]FGA showed significantly higher accumulation in the infected lung (5.2 ± 0.8%IA/cc) than in the uninfected lung (0.1 ± 0.0%IA/cc), further supporting its potential for imaging challenging clinical infections. Taken together, [¹⁸F]FGA PET may be a useful tool for pathogen-targeted imaging in clinical practice.