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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.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.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 ?-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 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.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.

SUBMITTER: Ordonez AA

PROVIDER: S-EPMC5209639 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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A Systematic Approach for Developing Bacteria-Specific Imaging Tracers.

Ordonez Alvaro A AA Weinstein Edward A EA Bambarger Lauren E LE Saini Vikram V Chang Yong S YS DeMarco Vincent P VP Klunk Mariah H MH Urbanowski Michael E ME Moulton Kimberly L KL Murawski Allison M AM Pokkali Supriya S Kalinda Alvin S AS Jain Sanjay K SK

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20160915 1

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.<h4>Methods</h4>We systematically screened 961 random radiolabeled molecules in silico as substrates for essential metab ...[more]

PMID: 27635025

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Project description:Background: Molecular targeting remains to be a promising approach in oncology. Overexpression of G protein-coupled receptors (GPCRs) in human cancer is offering a powerful opportunity for tumor-selective imaging and treatment employing nuclear medicine. We utilized novel chemerin-based peptide conjugates for chemokine-like receptor 1 (CMKLR1) targeting in a breast cancer xenograft model. Methods: By conjugation with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), we obtained a family of five highly specific, high-affinity tracers for hybrid positron emission tomography/magnetic resonance (PET/MR) imaging. A xenograft model with target-positive DU4475 and negative A549 tumors in immunodeficient nude mice enabled CMKLR1-specific imaging in vivo. We acquired small animal PET/MR images, assessed biodistribution by ex vivo measurements and investigated the tracer specificity by blocking experiments. Results: Five CMKLR1-targeting peptide tracers demonstrated high biological activity and affinity in vitro with EC50 and IC50 values below 2 nM. Our target-positive (DU4475) and target-negative (A549) xenograft model could be validated by ex vivo analysis of CMKLR1 expression and binding. After preliminary PET imaging, the three most promising tracers [68Ga]Ga-DOTA-AHX-CG34, [68Ga]Ga-DOTA-KCap-CG34 and [68Ga]Ga-DOTA-ADX-CG34 with best tumor uptake were further analyzed. Hybrid PET/MR imaging along with concomitant biodistribution studies revealed distinct CMKLR1-specific uptake (5.1% IA/g, 3.3% IA/g and 6.2% IA/g 1 h post-injection) of our targeted tracers in DU4475 tumor tissue. In addition, tumor uptake was blocked by excess of unlabeled peptide (6.4-fold, 5.5-fold and 3.4-fold 1 h post-injection), further confirming CMKLR1 specificity. Out of five tracers, we identified these three tracers with moderate, balanced hydrophilicity to be the most potent in receptor-mediated tumor targeting. Conclusion: We demonstrated the applicability of 68Ga-labeled peptide tracers by visualizing CMKLR1-positive breast cancer xenografts in PET/MR imaging, paving the way for developing them into theranostics for tumor treatment.

Dataset Information

A Systematic Approach for Developing Bacteria-Specific Imaging Tracers.

Publications

A Systematic Approach for Developing Bacteria-Specific Imaging Tracers.

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