Staphylococcus serine hydrolases as targets for therapeutic and imaging contrast agents

项目摘要 金黄色葡萄球菌是一种主要的人类病原体，是全球感染的主要原因。是 多种危及生命的疾病的病原体，包括菌血症，感染性心内膜炎， 骨髓炎、脓毒性关节炎和人工关节感染。治疗的一个主要并发症是 细菌可以形成生物膜并感染全身性抗生素施用难以到达的位置。 此外，根据感染部位、细菌负荷水平和感染部位的不同， 以及其他细菌物种可能参与感染。此外，S.金黄色葡萄球菌感染通常 更严重，管理更复杂，需要更多的干预措施， 其他细菌感染。因此，新的策略，快速和有效的诊断和治疗S。 金黄色葡萄球菌感染有可能具有显著的临床影响。这份提案概述了我们的计划， 小分子活性位点探针来鉴定由S.金黄色细菌。我们 相信分泌的或表面暴露的丝氨酸水解酶是新型小分子抗- 以及用于成像造影剂，其可用于非侵入性地可视化感染部位 in vivo.我们的初步工作已经确定了12个新的未表征的丝氨酸水解酶， 证实其中至少有一个参与宿主的毒力的某些方面。因此，我们的主要 目的是：1）对S.金黄色葡萄球菌，以确定最佳目标， 2）开发小分子造影剂和抑制剂， 选择性靶向参与发病机制的丝氨酸水解酶3）丝氨酸水解酶特异性成像 探针和抑制剂在小鼠感染模型中的作用。最终，这些目标的成功不仅会导致 S.金黄色葡萄球菌的发病机制， 成像工具和抑制剂的验证，然后可以在未来推进到临床应用。 最终，临床验证的成像和治疗剂具有影响检测、诊断和治疗的潜力。 治疗监测以及提供治疗感染的新方法。

Project Summary Staphylococcus aureus is a major human pathogen that is the leading cause of infections worldwide. It is the causative agent of multiple life threatening disease conditions including bacteremia, infectious endocarditis, osteomyelitis, septic arthritis and prosthetic joint infection. A major complication to treatment is the fact that the bacterium can form biofilms and infect locations that are hard to reach with systemic antibiotic administration. In addition, diagnosis can often be difficult depending on the location of the infection, level of bacterial burden and potential involvement of other bacterial species in the infection. Furthermore, S. aureus infections are often more severe and management more complicated with greater number of interventions required compared to other bacterial infections. Therefore novel strategies for rapid and effective diagnosis and treatment of S. aureus infections have the potential to have significant clinical impact. This proposal outlines our plans to use small molecule active site probes to identify serine hydrolases that are expressed by S. aureus bacteria. We believe that secreted or surface exposed serine hydrolases are ideal targets for both novel small molecule anti- virulence agents and for imaging contrast agents that can be used to non-invasively visualize sites of infection in vivo. Our preliminary efforts have already identified 12 new uncharacterized serine hydrolases and we have confirmed that at least one of these is involved in some aspect of virulence in the host. Therefore our primary aims are to 1) Functionally characterize serine hydrolases in S. aureus to identify optimal targets for imaging and therapeutic agents 2) Develop small molecule contrast agents and inhibitors that selectively target serine hydrolases involved in pathogenesis 3) Validate hydrolase-specific imaging probes and inhibitors in a mouse model of infection. Ultimately, success in these aims will not only lead to identification and functional characterization of novel regulators of S. aureus pathogenesis but also to the validation of imaging tools and inhibitors that could then be advanced to clinical applications in the future. Ultimately, clinical validated imaging and therapy agents have the potential to impact detection, diagnosis and therapy monitoring as well as to provide new ways to treat infection.