Sensing living P. aeruginosa using D-alanine derived radiotracers

使用 D-丙氨酸衍生的放射性示踪剂感测活的铜绿假单胞菌

• 批准号: 10230924
• 负责人: Joanne N. Engel
• 金额: $ 67.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10230924
• 关键词: Acute; Address; Adult; Alanine; Amino Acids; Antibiotic Therapy; Antibiotics; Automation; Bacteria; Bacterial Antibiotic Resistance; Bronchoalveolar Lavage; Bronchoscopy; Cell Nucleus; Cell Wall; Cells; Chronic; Clinical; Cystic Fibrosis; Data; Detection; Development; Diagnosis; Diagnostic Procedure; Disease; Drug resistance; Future; Goals; Gram-Positive Bacteria; High Pressure Liquid Chromatography; Human body; Image; Imaging Device; Imaging Techniques; Imaging technology; Immune response; In Vitro; Infection; Inflammatory; Label; Laboratories; Lead; Libraries; Lung; Magnetic Resonance; Mammalian Cell; Metabolic; Metabolic Pathway; Methods; Microbial Biofilms; Modeling; Morphology; Nuclear Magnetic Resonance; Organism; Pathogenicity; Patients; Peptidoglycan; Performance; Phase; Physicians; Pneumonia; Positron-Emission Tomography; Pre-Clinical Model; Process; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pseudomonas aeruginosa pneumonia; Radiopharmaceuticals; Reporting; Resistance; Saline; Science; Signal Transduction; Solid; Specificity; Sputum; Structure; Tissues; Tracer; Work; X-Ray Computed Tomography; acute infection; analog; base; chronic infection; clinical application; clinical translation; clinically translatable; cystic fibrosis patients; detection limit; fluorodeoxyglucose positron emission tomography; imaging modality; in vitro Model; in vivo; in vivo Model; in vivo monitoring; interest; liquid chromatography mass spectroscopy; metabolic imaging; microbiome; mimicry; mortality; mouse model; novel; pathogen; pathogenic bacteria; perpetrators; pneumonia treatment; pulmonary function decline; radiochemical; radiologist; radiotracer; treatment response; uptake

PROJECT SUMMARY: This application addresses a major challenge that radiologists and other physicians encounter frequently, namely distinguishing active infection from other processes in the human body. Specifically, the proposed work is motivated by the difficulty in diagnosing and treating pneumonias in cystic fibrosis patients, especially those caused by P. aeruginosa. Clinically available imaging tools either (1) are limited by their background accumulation in the lungs or (2) image the host response to infection rather than the living bacteria themselves. To address this challenge, we have developed several PET radiotracers that exploit metabolic pathways specific to bacteria, including D-amino acid derived probes most recently D-[3-11C]alanine. When D-[3-11C]alanine was applied to several compelling preclinical models of infection, we found that it was exquisitely sensitive to P. aeruginosa, which is not the case for the vast majority of reported radiotracers. We further showed that D-[3-11C]alanine is a radiotracer with (1) a simple, high-yield radiosynthesis (2) good in vivo stability (3) appropriate mimicry of the endogenous substrate (4) high rate of incorporation into both gram- negative and gram-positive bacteria and (5) low uptake in background tissues. These studies demonstrate the outstanding potential of D-[3-11C]alanine, with the proposed work necessary to further validate and understand this tracer. We will first expand our radiochemical methods, synthesizing the D-[1-11C]alanine isotopomer and structurally related 18F probes (Specific Aim 1). We will then further investigate the lead 11C isotopomer in vitro, analyzing its performance in clinical P. aeruginosa strains and validated biofilm models (Specific Aim 2). In Specific Aim 3, we will extend these concepts in vivo employing both acute and chronic models of P. aeruginosa infection.

项目摘要： 该应用程序解决了放射科医生和其他医生经常遇到的重大挑战， 即将主动感染与人体其他过程区分开。具体而言，拟议的工作 是由于难以诊断和治疗囊性纤维化患者的肺炎的动机，尤其是那些 由铜绿假单胞菌引起。临床上可用的成像工具（1）受其背景的限制 在肺部积聚或（2）图像宿主对感染的反应，而不是活细菌本身。 为了应对这一挑战，我们开发了几种利用代谢途径的宠物放射性示例 特定于细菌，包括D-氨基酸衍生的探针最近的D- [3-11c]丙氨酸。 当将D- [3-11c]丙氨酸应用于几种引人注目的临床前感染模型时，我们发现它是 对铜绿假单胞菌非常敏感，对于绝大多数报告的放射性示例并非如此。我们 进一步表明，d- [3-11c]丙氨酸是一种放射性示例，具有（1）简单的高收益放射性合成（2）体内良好 稳定性（3）内源性底物的适当模仿（4）高度掺入两个ram- 阴性和革兰氏阳性细菌以及（5）背景组织中的摄取量低。这些研究表明 D- [3-11c]丙氨酸的杰出潜力，并具有进一步验证和了解的拟议工作 这个示踪剂。我们将首先扩展放射化学方法，合成D- [1-11c]丙氨酸同位素和 与结构相关的18F探针（特定目标1）。然后，我们将进一步研究铅11c同位素 体外，分析了其在临床铜绿假单胞菌菌株中的性能和经过验证的生物膜模型（特定的目标2）。 在特定的目标3中，我们将使用P的急性和慢性模型扩展这些概念。 铜绿感染。