Pathogen specific imaging of endocarditis

心内膜炎的病原体特异性成像

• 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
• 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

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（应用程序提供）：急性心内膜炎的临床管理，心脏瓣膜的经常和致命感染（高达47％的死亡率）仍然受到高度挑战，并且通常失败了1,2。急性心内膜炎中最常见的病原体是金黄色葡萄球菌，其次是链球菌种类2,3。未满足的临床需求包括：（i）可靠的诊断或排除心内膜炎，（ii）病原体的特定鉴定，告知抗生素选择的选择，以及（iii）获取定量数据以指导手术干预。在这里，我们旨在开发一种临床上可行的新方法，用于黄金葡萄球菌心内膜炎的病原体特异性成像。我们的策略是基于细菌分泌的病毒因子葡萄球菌的超高亲和力（17pm）5，用于凝血酶原（prot），并使用这种相互作用来开发特定的成像探针6。葡萄球菌酶的NH2-末端D1和D2域与凝血酶（或Prot成像平台）结合，而COOH末端重复区域同时结合了纤维蛋白原。因此，葡萄球菌酶首先将成像探针固定在心内城植被中。我们的初步数据表明，利用蛋白质和葡萄球菌酶之间的高亲和力用于工程成像剂是可行的（NatureMed。2011）6。我们使用凝血酶原的激活袋，该激活袋通过称为“分子性别”（Bode and Huber 1976）7作为亲和力配体，与葡萄球菌酶紧密结合。用荧光色素标记蛋白酶的丝氨酸蛋白酶活性位点使我们能够在带有光学成像的小鼠模型中检测和监测金黄色葡萄球菌心内膜炎6。此外，我们合成了金黄色葡萄球菌（64cu-iprot）的宠物记者，并发现葡萄球菌酶的敏感宠物成像也是可行的。第一个目的提出的研究基于这种已经建立的成像剂，但还将追求针对其他细菌菌株的替代成像剂的开发。第二个目的描述了使用点击化学使用优化的药代动力学开发18F化合物，我们最近采用了宠物代理的便利合成8,9。我们将在G面中测试两种铅化合物，我们将采用这些问题来通过杂交ECG触发的PET/CT和PET/MRI来对鼠心内膜炎进行成像，从而将敏感的分子模态（PET）与评估左心室功能的主要方式相结合，这也可以检测瓣膜不足（MRI）。代理开发将集中于解决优先级紧急医疗需求的临床可行性，其最终目的是使用瓣膜病变中细菌的PET/MRI检测来诊断患者急性心内膜炎。