A Systematic Approach for Developing Bacteria-Specific Imaging Tracers

Abstract

The modern patient is increasingly susceptible to bacterial infections including those due to multi-drug 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 positron emission tomography (PET)-based imaging tracers, were evaluated in a murine myositis model. Results We identified three novel, non-toxic molecules demonstrating selective bacterial uptake: para-aminobenzoic acid (PABA), with uptake in all representative bacteria including Mycobacterium tuberculosis; mannitol, with selectively 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 three molecules rapidly accumulated in respective clinical isolates of interest including MDROs such as methicillin resistant S. aureus (MRSA), extended-spectrum beta-lactamase (ESBL)-producing, and carbapenem-resistant Enterobacteriaceae. In a murine myositis model, fluorine-labeled analogs of all three 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 from 2-deoxy-2-[F-18]fluoro-D-glucose (18F-FDG). PET, utilizing 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.

[11C]Para-Aminobenzoic Acid: A Positron Emission Tomography Tracer Targeting Bacteria-Specific Metabolism

“…One major strength is the broad sensitivity of PABA for human pathogens. 3 H-PABA has shown incorporation into model pathogens representing several important bacterial classes: S. aureus (gram-positive), E. coli (gram-negative, Enterobacteriaceae), Pseudomonas aeruginosa (gram-negative, non-Enterobacteriaceae), and mycobacteria 20 . Another potential strength is the short half-life of [ 11 C]PABA (~20 minutes), which could allow repeat tracer doses (and imaging) over a short time interval.…”

“…PABA is U.S. Food and Drug Administration (FDA) approved as a sunscreen and an oral medication, and thus its safety in humans is well-established 19 . These qualities and results from our prior studies led us to hypothesize that radio-labelled PABA would be an excellent candidate for imaging bacterial infections 20 . Moreover, we have also demonstrated, via commercially available [ 3 H]PABA, rapid incorporation (minutes) into an extended bacterial panel of laboratory strains, and clinical isolates including multidrug resistant organisms (MDROs) such as methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and carbapenem-resistant Enterobacteriaceae (CRE) strains 20 .…”

Microglia activation in a pediatric rabbit model of tuberculous meningitis

“…First-in-human studies using 124 I-DPA-713 are currently ongoing. Pathogen-specific imaging modalities to specifically detect bacteria directly could also substantially enhance the diagnostic and monitoring capabilities (Ordonez et al, 2016b; Weinstein et al, 2014) and could be tested in this model in future studies. MRI could also be utilized to monitor response to treatment or predict outcomes.…”

Specific Imaging of Bacterial Infection Using 6″-18F-Fluoromaltotriose: A Second-Generation PET Tracer Targeting the Maltodextrin Transporter in Bacteria

“…Also, just as 18 F-FDG cannot distinguish between different types of cancers, 6$-18 F-fluoromaltotriose cannot distinguish between different types of bacterial strains. Tracers under investigation, such as 18 Ffluorodeoxysorbitol and others (30), which are internalized by specific bacterial pathogens, might be used in conjunction to complete the diagnosis when clinically necessary. In contrast to 18 F-FDG, however, 6$-18 F-fluoromaltotriose can apparently distinguish infection from inflammation (Fig.…”