Siderophore based molecular imaging of pulmonary infections

项目总结 慢性阻塞性肺疾病(COPD)是一种进行性、衰弱的呼吸系统疾病，临床上 间歇性急性加重(AECOPD)，从自限性发作到华丽发作 呼吸衰竭。AECOPD最常由病毒和/或细菌感染引起。细菌 在AECOPD中通常起致病作用的微生物有假单胞菌、克雷伯氏菌、不动杆菌和 肠杆菌、多重耐药假单胞菌和肺炎克雷伯菌是引起肺炎的常见原因 慢性阻塞性肺疾病住院患者继发肺炎。痰的颜色变化表明 通常被用作细菌感染存在的替代标志的脓肿是一种晚期的、不一致的、 非特异性和不敏感的生物标志物；它不能区分病毒和细菌感染，以及许多 AECOPD患者根本不会排痰。有针对性的、特定于病原体的和 灵敏的成像方式，可以检测下呼吸道中的细菌并区分细菌和病毒 非侵袭性感染将促进我们对AECOPD的理解，促进先发制人的发展 治疗范例。在这项提案中，我们打算将这些独特的细菌膜转运蛋白用于 细菌及其不同的金属载体作为PET报告探针定位和鉴定病原活菌 在AECOPD。我们还将评估长袍在鉴定联合感染中细菌的特异性和敏感性。 流感病毒(H3N2)感染模型。我们将进一步评估PET成像的响应性 不同抗生素对肺炎克雷伯菌和铜绿假单胞菌临床分离株的影响。 如果成功，这些探针将能够帮助识别住院患者的亚临床细菌定植。 通过AECOPD，来确定最终导致感染的细菌是否是相同的菌株 这被发现是殖民行为。该项目将为将开放的新技术平台奠定基础 探索使用不同的金属载体阵列作为造影剂的可能性的途径 病原体感染的全部曲目。

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating respiratory condition with a clinical course that is punctuated by acute exacerbations (AECOPD) ranging from self-limited episodes to florid respiratory failure. AECOPD are most often precipitated by viral and/or bacterial infections. The bacterial organisms that commonly play pathogenic role in AECOPD are Pseudomonas, Klebsiella, Acinetobacter, and Enterobacter, and multidrug resistant Pseudomonas and Klebsiella pneumoniae are a common cause of secondary pneumonias in hospitalized patients with COPD. The change in color of sputum indicative of purulence that is often used as a surrogate marker for the presence of bacterial infection is a late, inconsistent, nonspecific and insensitive biomarker; it cannot distinguish between viral and bacterial infection, and many patients with AECOPD do not produce sputum at all. The availability of a targeted, pathogen-specific and sensitive imaging modality that could detect bacteria in the lower airways and differentiation bacterial from viral infection non-invasively would advance our understanding of AECOPD and facilitate development of preemptive treatment paradigms. In this proposal, we intend on using these unique bacterial membrane transporters on bacteria, and their distinct metallophores as PET reporter probes to localize and identify pathogenic live bacteria in AECOPD. We will also evaluate the specificity and sensitivity of the robes in identifying the bacteria in co- infection models with influenza virus (H3N2). We will further evaluate the responsiveness of the PET imaging probe and modality to different antibiotics, against several clinical isolates of K. pneumoniae and P. aeruginosa. If successful, the probes would be able to assist with identifying subclinical bacterial colonization of in patients with AECOPD, to determine if the bacteria that are ultimately responsible for the infection are the same strains that was found to be colonizing. This project will lay the foundation for a new technology platform that will open avenues to explore the possibility of using the diverse array of metallophores as contrast agents for imaging the entire repertoire of pathogenic infections.