TY - JOUR
T1 - A systematic approach for developing bacteria-specific imaging tracers
AU - Ordonez, Alvaro A.
AU - Weinstein, Edward A.
AU - Bambarger, Lauren E.
AU - Saini, Vikram
AU - Chang, Yong S.
AU - DeMarco, Vincent P.
AU - Klunk, Mariah H.
AU - Urbanowski, Michael E.
AU - Moulton, Kimberly L.
AU - Murawski, Allison M.
AU - Pokkali, Supriya
AU - Kalinda, Alvin S.
AU - Jain, Sanjay K.
N1 - Publisher Copyright:
© COPYRIGHT 2017 by the Society of Nuclear Medicine and Molecular Imaging.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - Bacteria
KW - Drug-resistance
KW - Imaging
KW - PET
KW - Translational
UR - http://www.scopus.com/inward/record.url?scp=85009083891&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85009083891&partnerID=8YFLogxK
U2 - 10.2967/jnumed.116.181792
DO - 10.2967/jnumed.116.181792
M3 - Article
C2 - 27635025
AN - SCOPUS:85009083891
SN - 0161-5505
VL - 58
SP - 144
EP - 150
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 1
ER -