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.
We propose to develop a clinically viable, novel method for pathogen-specific imaging of Staphylococcus aureus endocarditis. We will employ high affinity PET probes to image murine endocarditis by hybrid PET/MRI. Agent development will focus on clinical feasibility, with the ultimate goal of using PET/MRI detection of staphylocoagulase in valve lesions for the diagnosis of acute endocarditis in patients.
|Huang, Jiansheng; Milton, Amber; Arnold, Robert D et al. (2016) Methods for measuring myeloperoxidase activity toward assessing inhibitor efficacy in living systems. J Leukoc Biol 99:541-8|
|Sager, Hendrik B; Dutta, Partha; Dahlman, James E et al. (2016) RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction. Sci Transl Med 8:342ra80|
|Davis 4th, Richard W; Brannen, Andrew D; Hossain, Mohammad J et al. (2016) Complete genome of Staphylococcus aureus Tager 104 provides evidence of its relation to modern systemic hospital-acquired strains. BMC Genomics 17:179|
|Nahrendorf, Matthias; Frantz, Stefan; Swirski, Filip K et al. (2015) Imaging systemic inflammatory networks in ischemic heart disease. J Am Coll Cardiol 65:1583-91|
|Sager, Hendrik B; Heidt, Timo; Hulsmans, Maarten et al. (2015) Targeting Interleukin-1Î² Reduces Leukocyte Production After Acute Myocardial Infarction. Circulation 132:1880-90|
|Leuschner, Florian; Courties, Gabriel; Dutta, Partha et al. (2015) Silencing of CCR2 in myocarditis. Eur Heart J 36:1478-88|
|Dutta, Partha; Hoyer, Friedrich Felix; Grigoryeva, Lubov S et al. (2015) Macrophages retain hematopoietic stem cells in the spleen via VCAM-1. J Exp Med 212:497-512|
|Huang, Jiansheng; Smith, Forrest; Panizzi, Jennifer R et al. (2015) Inactivation of myeloperoxidase by benzoic acid hydrazide. Arch Biochem Biophys 570:14-22|
|Dutta, Partha; Nahrendorf, Matthias (2015) Monocytes in myocardial infarction. Arterioscler Thromb Vasc Biol 35:1066-70|
|Courties, Gabriel; Herisson, Fanny; Sager, Hendrik B et al. (2015) Ischemic stroke activates hematopoietic bone marrow stem cells. Circ Res 116:407-17|
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