title: A Systematic Approach for Developing Bacteria-Specific Imaging Tracers.
abstract: The modern patient is increasingly susceptible to bacterial infections including those due to multidrug-resistant organisms (MDROs). Noninvasive whole-body analysis with pathogen-specific imaging technologies can significantly improve patient outcomes by rapidly identifying a source of infection and monitoring the response to treatment, but no such technology exists clinically.
  
  
  METHODS
  We systematically screened 961 random radiolabeled molecules in silico as substrates for essential metabolic pathways in bacteria, followed by in vitro uptake in representative bacteria-Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and mycobacteria. Fluorine-labeled analogs, that could be developed as PET-based imaging tracers, were evaluated in a murine myositis model.
  
  
  RESULTS
  We identified 3 novel, nontoxic molecules demonstrating selective bacterial uptake: para-aminobenzoic acid (PABA), with uptake in all representative bacteria including Mycobacterium tuberculosis; mannitol, with selective uptake in S. aureus and E. coli; and sorbitol, accumulating only in E. coli None accumulated in mammalian cells or heat-killed bacteria, suggesting metabolism-derived specificity. In addition to an extended bacterial panel of laboratory strains, all 3 molecules rapidly accumulated in respective clinical isolates of interest including MDROs such as methicillin-resistant S. aureus, extended-spectrum β-lactamase-producing, and carbapenem-resistant Enterobacteriaceae. In a murine myositis model, fluorine-labeled analogs of all 3 molecules could rapidly detect and differentiate infection sites from sterile inflammation in mice (P = 0.03). Finally, 2-deoxy-2-[F-18]fluoro-d-sorbitol (18F-FDS) can be easily synthesized from18F-FDG. PET, with18F-FDS synthesized using current good manufacturing practice, could rapidly differentiate true infection from sterile inflammation to selectively localize E. coli infection in mice.
  
  
  CONCLUSIONS
  We have developed a systematic approach that exploits unique biochemical pathways in bacteria to develop novel pathogen-specific imaging tracers. These tracers have significant potential for clinical translation to specifically detect and localize a broad range of bacteria, including MDROs.
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Alvaro A
authors.initials: AA
authors.lastname: Ordonez
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Weinstein
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Bambarger
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Vikram
authors.initials: V
authors.lastname: Saini
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Yong S
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Vincent P
authors.initials: VP
authors.lastname: DeMarco
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Mariah H
authors.initials: MH
authors.lastname: Klunk
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Urbanowski
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Moulton
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Murawski
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Supriya
authors.initials: S
authors.lastname: Pokkali
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Alvin S
authors.initials: AS
authors.lastname: Kalinda
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland sjain5@jhmi.edu.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Jain
mesh_terms: D010129:4-Aminobenzoic Acid / Q000493:pharmacokinetics*; D001419:Bacteria / Q000145:classification / Q000166:cytology / Q000378:metabolism*; D001424:Bacterial Infections / Q000000981:diagnostic imaging* / Q000382:microbiology*; D007553:Isotope Labeling / Q000379:methods; D008353:Mannitol / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013012:Sorbitol / Q000493:pharmacokinetics*
chemical_list: D019275:Radiopharmaceuticals; D008353:Mannitol; D013012:Sorbitol; D010129:4-Aminobenzoic Acid
keywords: PET; bacteria; drug-resistance; imaging; translational