Novel Imaging Tracers for Rapid and Noninvasive Assessment of Bacterial Infection

描述（由申请人提供）：无创成像是早期诊断和监测各种疾病过程的强大临床工具。由于分子和细胞的改变在病理过程中比结构改变发生得更早，下一代分子成像为观察感染提供了无与伦比的机会。这种快速发展的技术已经成为肿瘤学领域的重要工具，在传染病领域也具有类似的潜力。利用小分子选择性培养基进行微生物分化是临床微生物学研究的主要内容。然而，目前诊断和监测感染的工具依赖于对可疑部位进行取样，然后进行培养或分子技术。这种方法有几个局限性——侵入性、危险、耗时、取样错误和污染。我们利用细菌中存在的独特生化途径，开发了一种用于检测、量化和监测细菌感染的新型特异性成像示踪剂管道。为了证明这一概念，我们系统地筛选了400个随机的14C和3H标记的化合物库，用于细菌（而不是宿主细胞）的代谢和摄取。从这个文库中，我们随后开发了成像示踪剂，可以区分细菌感染和非感染过程，也可以区分细菌类别。我们的中心假设是，由原核特异性途径代谢的小分子（而不是宿主细胞）可以发展成细菌特异性成像示踪剂，可以区分感染和非感染过程，并提供引起感染的细菌类别的信息。我们建议开展多学科合作，开发一系列新型成像示踪剂，用于快速和无创地评估细菌感染，这将为检测和区分广泛的致病菌提供一个全面的平台。此外，我们还建议发展成像作为研究抗菌药物多室药代动力学的平台。这些技术是一个新兴的研究领域，克服了现有工具的几个基本限制，并将对基础研究和患者护理产生广泛的影响。除了诊断和监测疾病，这些技术还将为动物研究提供统一的跨物种平台；对疾病发病机制有独特的见解；加快新疗法从临床到临床的转化。最后，由于分子成像很容易用于人类，经过验证的示踪剂将成为临床应用的宝贵工具，并使传染病的个性化医疗成为可能。

DESCRIPTION (provided by applicant): 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.