Pathogen specific imaging of endocarditis

心内膜炎的病原体特异性成像

基本信息

批准号：
8496960
负责人：
Matthias Nahrendorf
金额：
$ 41.97万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8496960
关键词：
Active Sites Acute Endocarditis Address Adopted Affinity Anatomy Antibiotic Therapy Antibiotics Bacteremia Bacteria Bacterial Endocarditis Binding Bioluminescence Blood Blood Circulation Brain Cardiac Catheters Cessation of life Chemistry Cine Magnetic Resonance Imaging Clinical Clinical Management Data Detection Development Diagnosis Dose Drug Kinetics Electrocardiogram Embolism Endocarditis Engineering Exclusion Fever Fibrinogen Fluorochrome Goals Half-Life Heart Valves Heart murmur Human Hybrids Image Infection Infective endocarditis Injection of therapeutic agent Isotopes Label Lead Left Ventricular Function Lesion Life Ligands Lung Magnetic Resonance Imaging Medical Methods Miniature Swine Minor Modality Modeling Molecular Monitor Mus N-terminal Nature Operative Surgical Procedures Optics PET/CT scan Patients Plasminogen Population Dynamics Positron-Emission Tomography Prothrombin Recurrent disease Reporter Sensitivity and Specificity Serine Protease Sexuality Signal Transduction Staphylocoagulase Staphylococcus aureus Streptococcus Streptokinase Terminal Repeat Sequences Testing Thrombin Time Translations Treatment Efficacy Vancomycin Virulence Factors Withdrawal aortic valve base clinical Diagnosis cycloaddition diagnostic accuracy imaging probe improved killings mortality mouse model novel pathogen public health relevance sensor septic valvular insufficiency

项目摘要

DESCRIPTION (provided by applicant): Clinical management of acute endocarditis, a frequent and deadly infection of the heart valves (mortality of up to 47%), remains highly challenging and often unsuccessful1,2. The most common pathogen in acute endocarditis is Staphylococcus aureus, followed by streptococcus species2,3. Unmet clinical needs include: (i) reliable diagnosis or exclusion of endocarditis, (ii) specific identification of the pathogen informing selection of antibiotics, and (iii) acquisition of quantitative data to guide surgical intervention. Here we aim to develop a clinically viable, novel method for pathogen-specific imaging of Staphylococcus aureus endocarditis. Our strategy is based on the ultrahigh affinity (17pM)5 of the virulence factor staphylocoagulase, which is secreted by the bacteria, to prothrombin (ProT) and the use of this interaction to develop specific imaging probes6. Staphylocoagulase's NH2-terminal D1 and D2-domains bind to thrombin (or the ProT imaging platform), while the COOH-terminal repeats region binds to fibrinogen at the same time. Therefore, staphylocoagulase firmly anchors the imaging probe in endocarditic vegetations. Our preliminary data show that harnessing the high affinity between ProT and staphylocoagulase for engineering imaging agents is feasible (Nature Med. 2011)6. We used prothrombin's activation pocket that tightly binds to staphylocoagulase by a mechanism dubbed "molecular sexuality" (Bode and Huber 1976)7 as an affinity ligand. Labeling ProT's serine protease active site with a fluorochrome allowed us to detect and monitor S. aureus endocarditis in a mouse model with optical imaging6. Furthermore, we synthesized a PET reporter for S. aureus (64Cu-iProT) and found that sensitive PET imaging of staphylocoagulase is also feasible. The studies proposed in the first aim are based on this already-established imaging agent but will also pursue development of alternative imaging agents targeted to other bacterial strains. The second aim describes developing 18F compounds with optimized pharmacokinetics using click chemistry, which we recently adopted for facile synthesis of PET agents8,9. Two lead compounds will be tested in a G¿ttingen minipig model of endocarditis. We will employ these probes to image murine endocarditis by hybrid ECG- triggered PET/CT and PET/MRI, thereby combining a sensitive molecular modality (PET) with a leading modality for assessing left ventricular function which can also detect valvular insufficiency (MRI). Agent development will focus on clinical feasibility to address the aforementioned urgent medical needs, with the ultimate goal of using PET/MRI detection of bacteria in valve lesions for the diagnosis of acute endocarditis in patients.

描述（由申请人提供）：急性心内膜炎是一种常见且致命的心脏瓣膜感染（死亡率高达 47%），其临床治疗仍然极具挑战性且常常不成功1,2 急性心内膜炎最常见的病原体是金黄色葡萄球菌。，其次是链球菌属2,3 未满足的临床需求包括：(i) 可靠诊断或排除心内膜炎，(ii) 明确病原体，以选择抗生素，以及(iii) 获取定量数据以指导手术干预。我们的目标是开发一种临床上可行的金黄色葡萄球菌心内膜炎病原体特异性成像方法。我们的策略基于毒力因子葡萄球菌凝固酶的超高亲和力 (17pM)5。由细菌分泌的凝血酶原 (ProT)，并利用这种相互作用开发特异性成像探针 6。 NH2 末端 D1 和 D2 结构域与凝血酶（或 ProT 成像平台）结合，而 COOH 末端重复区域同时与纤维蛋白原结合，因此，葡萄球菌凝固酶将成像探针牢固地锚定在心内膜赘生物中。利用 ProT 和葡萄球菌凝固酶之间的高亲和力来设计显像剂是可行的（Nature Med. 2011）6。凝血酶原的激活口袋通过一种被称为“分子性”的机制（Bode 和 Huber 1976）7 作为亲和配体与葡萄球菌凝固酶紧密结合，用荧光染料标记 ProT 的丝氨酸蛋白酶活性位点使我们能够检测和监测小鼠的金黄色葡萄球菌心内膜炎。此外，我们合成了金黄色葡萄球菌 (64Cu-iProT) 的 PET 报告基因，并发现第一个目标中提出的研究基于这种已经建立的显像剂，但也将致力于开发针对其他细菌菌株的替代显像剂，第二个目标描述了开发具有优化药代动力学的 18F 化合物。使用点击化学，我们最近采用该化学来轻松合成 PET 试剂8,9 将在 G¿ 中测试两种先导化合物。我们将使用这些探针通过混合心电图触发的 PET/CT 和 PET/MRI 对小鼠心内膜炎进行成像，从而将敏感的分子模式 (PET) 与评估左心室功能的主要模式相结合。瓣膜关闭不全（MRI）药物的开发将侧重于临床可行性，以满足紧急的医疗需求，最终目标是利用 PET/MRI 检测瓣膜病变中的细菌来诊断急性瓣膜关闭不全。心内膜炎患者。