Siderophore based molecular imaging of pulmonary infections

基于铁载体的肺部感染分子成像

• 批准号: 10736423
• 负责人: Nalinikanth Kotagiri
• 金额: $ 67.89万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736423
• 关键词: Acinetobacter; Acute; Affinity; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Bacterial Model; Binding; Biodistribution; Biological Markers; Chronic Obstructive Pulmonary Disease; Clinical; Color; Communicable Diseases; Complex; Contrast Media; Copper; Detection; Development; Differential Diagnosis; Disease; Disease model; Enterobacter; Enterobacteriaceae; Exhibits; Family; Foundations; Goals; Gram-Negative Bacteria; Hospitalization; Imaging Device; Infection; Influenza A Virus, H3N2 Subtype; Innate Immune System; Iron; Klebsiella; Klebsiella pneumoniae; Label; Ligands; Lung; Lung infections; Membrane; Membrane Transport Proteins; Metals; Modeling; Monitor; Morbidity - disease rate; Multi-Drug Resistance; Mus; Myositis; Organism; Pathogenicity; Patients; Performance; Play; Pneumonia; Positron-Emission Tomography; Property; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas aeruginosa pneumonia; Radioisotopes; Reporter; Respiratory Failure; Role; Sensitivity and Specificity; Siderophores; Specimen; Sputum; Surrogate Markers; Techniques; Time; Treatment Cost; Treatment Efficacy; Viral; Virus Diseases; X-Ray Computed Tomography; clinically relevant; co-infection; imaging agent; imaging modality; imaging probe; improved; in vivo; in vivo evaluation; influenzavirus; innovation; metal chelator; molecular imaging; mortality; mouse model; new technology; nuclear imaging; pathogen; pyochelin; quantitative imaging; real-time images; receptor; respiratory; screening; technology platform; uptake; yersiniabactin

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.

项目概要 慢性阻塞性肺疾病 (COPD) 是一种进行性、使人衰弱的呼吸系统疾病，临床上 不时出现急性加重 (AECOPD) 的病程，范围从自限性发作到剧烈发作 呼吸衰竭。 AECOPD 最常由病毒和/或细菌感染引起。细菌 通常在 AECOPD 中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。 住院 COPD 患者的继发性肺炎。痰液颜色的变化表明 化脓通常被用作细菌感染存在的替代标志，是一种晚期的、不一致的、 非特异性和不敏感的生物标志物；它无法区分病毒感染和细菌感染，并且许多 AECOPD 患者根本不产生痰。具有针对性、病原体特异性和 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 非侵入性感染将增进我们对 AECOPD 的理解，并促进先发制人的发展 治疗范式。在这个提案中，我们打算使用这些独特的细菌膜转运蛋白 细菌及其独特的金属载体作为 PET 报告探针来定位和识别致病性活细菌 在 AECOPD 中。我们还将评估长袍在识别共同细菌中的特异性和敏感性。 流感病毒（H3N2）感染模型。我们将进一步评估 PET 成像的反应性 针对肺炎克雷伯菌和铜绿假单胞菌的几种临床分离株的不同抗生素的探针和方式。 如果成功，探针将能够帮助识别患者体内的亚临床细菌定植 与 AECOPD 一起，确定最终导致感染的细菌是否是同一菌株 被发现正在殖民。该项目将为即将开放的新技术平台奠定基础 探索使用多种金属团作为造影剂进行成像的可能性的途径 病原体感染的全部内容。