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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Ordonez, Alvaro A; Weinstein, Edward A; Bambarger, Lauren E et al. (2016) A Systematic Approach for Developing Bacteria-Specific Imaging Tracers. J Nucl Med :
Ordonez, Alvaro A; Tasneen, Rokeya; Pokkali, Supriya et al. (2016) Mouse model of pulmonary cavitary tuberculosis and expression of matrix metalloproteinase-9. Dis Model Mech 9:779-88
DeMarco, Vincent P; Ordonez, Alvaro A; Klunk, Mariah et al. (2015) Determination of [11C]rifampin pharmacokinetics within Mycobacterium tuberculosis-infected mice by using dynamic positron emission tomography bioimaging. Antimicrob Agents Chemother 59:5768-74
Salazar-Austin, Nicole; Ordonez, Alvaro A; Hsu, Alice Jenh et al. (2015) Extensively drug-resistant tuberculosis in a young child after travel to India. Lancet Infect Dis 15:1485-91
Xu, Ziyue; Bagci, Ulas; Mansoor, Awais et al. (2015) Computer-aided pulmonary image analysis in small animal models. Med Phys 42:3896-910
Ordonez, Alvaro A; DeMarco, Vincent P; Klunk, Mariah H et al. (2015) Imaging Chronic Tuberculous Lesions Using Sodium [(18)F]Fluoride Positron Emission Tomography in Mice. Mol Imaging Biol 17:609-14
Xu, Ziyue; Bagci, Ulas; Jonsson, Colleen et al. (2014) Efficient ribcage segmentation from CT scans using shape features. Conf Proc IEEE Eng Med Biol Soc 2014:2899-902
Pokkali, Supriya; Jain, Sanjay (2013) Novel vaccine strategies against tuberculosis: a road less travelled. Expert Rev Vaccines 12:1373-5