Non-invasive imaging is a powerful clinical tool for the early diagnosis, and monitoring of various disease processes. Next generation molecular imaging promises unparalleled opportunities for visualizing infections since molecular and cellular alterations occur earlier in a pathologic process, than structural changes. This rapidly developing technology has already become an essential tool in the field of oncology, with similar potential for infectious diseases. Differentiation of microbes by selective growth media, utilizin small molecules, is a mainstay of clinical microbiology. However, current tools to diagnose and monitor infections are dependent upon sampling suspected sites, and then performing culture or molecular techniques. This approach has several limitations - invasive, often dangerous, time consuming, and subject to incorrect sampling and contamination. We have exploited the unique biochemical pathways present within bacteria to develop a pipeline of novel and specific imaging tracers for detecting, quantifying and monitoring bacterial infections. As proof of concept, we systematically screened a library of 400 random 14C and 3H labeled compounds for metabolism and uptake by bacteria (but not host cells). From this library, we subsequently developed imaging tracers that could differentiate bacterial infections from non-infectious processes, and also allow discrimination between bacterial classes. Our central hypothesis is that small molecules metabolized by prokaryotic-specific pathways (but not host cells), could be developed into bacteria-specific imaging tracers that could differentiate infections from non-infectious processes and also provide information on the bacterial class causing the infection. We propose a multi-disciplinary collaboration, for developing a pipeline of novel imaging tracers for rapid and noninvasive assessment of bacterial infections that will provide a comprehensive platform to detect and discriminate a wide spectrum of pathogenic bacteria. In addition, we also propose the development of imaging as a platform to study multi-compartment pharmacokinetics of antimicrobial drugs. These technologies are an emerging field of research, overcome several fundamental limitations of current tools, and will have a broad impact on both basic research and patient care. Beyond diagnosis and monitoring disease, these technologies will also provide a uniform cross-species platform for animal studies;allow unique insights into understanding disease pathogenesis;and expedite bench-to-bedside translation of new therapeutics. Finally, since molecular imaging is readily available for humans, validated tracers will become valuable tools for clinical applications, and for enabling personalized medicine for infectious diseases.

Public Health Relevance

Our overall goals are to develop novel imaging tracers for rapid and noninvasive assessment of bacterial infections and to study antimicrobial pharmacokinetics. These technologies are an emerging field of research, overcome several fundamental limitations of current tools, and will have a broad impact to both basic research and patient care.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-A (51))
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Sastre, Antonio
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Johns Hopkins University
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United States
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Sanchez-Bautista, Julian; Foss, Catherine A; Ordonez, Alvaro A et al. (2018) Imaging Pulmonary Foreign Body Reaction Using [125I]iodo-DPA-713 SPECT/CT in Mice. Mol Imaging Biol :
Mutch, Christopher A; Ordonez, Alvaro A; Qin, Hecong et al. (2018) [11C]Para-Aminobenzoic Acid: A Positron Emission Tomography Tracer Targeting Bacteria-Specific Metabolism. ACS Infect Dis 4:1067-1072
Foss, Catherine A; Sanchez-Bautista, Julian; Jain, Sanjay K (2018) Imaging Macrophage-associated Inflammation. Semin Nucl Med 48:242-245
Tucker, Elizabeth W; Guglieri-Lopez, Beatriz; Ordonez, Alvaro A et al. (2018) Noninvasive 11C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis. Sci Transl Med 10:
Holt, Daniel P; Kalinda, Alvin S; Bambarger, Lauren E et al. (2018) Radiosynthesis and validation of [Carboxy-11 C]4-Aminobenzoic acid ([11 C]PABA), a PET radiotracer for imaging bacterial infections. J Labelled Comp Radiopharm :
Zhang, Zhuo; Ordonez, Alvaro A; Wang, Hui et al. (2018) Positron Emission Tomography Imaging with 2-[18F]F- p-Aminobenzoic Acid Detects Staphylococcus aureus Infections and Monitors Drug Response. ACS Infect Dis 4:1635-1644
Ordonez, Alvaro A; Jain, Sanjay K (2018) Pathogen-Specific Bacterial Imaging in Nuclear Medicine. Semin Nucl Med 48:182-194
Ordonez, Alvaro A; Pokkali, Supriya; Sanchez-Bautista, Julian et al. (2018) Matrix Metalloproteinase Inhibition in a Murine Model of Cavitary Tuberculosis Paradoxically Worsens Pathology. J Infect Dis :
Jain, Sanjay K; Tobin, David M; Tucker, Elizabeth W et al. (2018) Tuberculous meningitis: a roadmap for advancing basic and translational research. Nat Immunol 19:521-525
Rifat, Dalin; Prideaux, Brendan; Savic, Radojka M et al. (2018) Pharmacokinetics of rifapentine and rifampin in a rabbit model of tuberculosis and correlation with clinical trial data. Sci Transl Med 10:

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