A systematic approach for developing bacteria-specific imaging tracers

Alvaro Ordonez Suarez, Edward A. Weinstein, Lauren E. Bambarger, Vikram Saini, Yong S. Chang, Vincent P. DeMarco, Mariah H. Klunk, Michael E. Urbanowski, Kimberly L. Moulton, Allison M. Murawski, Supriya Pokkali, Alvin S. Kalinda, Sanjay Jain

Research output: Contribution to journalArticle

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 b-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 5 0.03). Finally, 2-deoxy-2-[F-18]fluoro-D-sorbitol (18F-FDS) can be easily synthesized from 18F-FDG. PET, with 18F-FDS synthesized using current good manufacturing practice, could rapidly differentiate true infection from sterile inflammation to selectively localize E. coli infection in mice. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)144-150
Number of pages7
JournalJournal of Nuclear Medicine
Volume58
Issue number1
DOIs
StatePublished - Jan 1 2017

Keywords

  • Bacteria
  • Drug-resistance
  • Imaging
  • PET
  • Translational

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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    Ordonez Suarez, A., Weinstein, E. A., Bambarger, L. E., Saini, V., Chang, Y. S., DeMarco, V. P., Klunk, M. H., Urbanowski, M. E., Moulton, K. L., Murawski, A. M., Pokkali, S., Kalinda, A. S., & Jain, S. (2017). A systematic approach for developing bacteria-specific imaging tracers. Journal of Nuclear Medicine, 58(1), 144-150. https://doi.org/10.2967/jnumed.116.181792