SYNTHESIS OF CATIONIC STEROID COMPOUNDS FOR DETECTION OF BACTERIAL INFECTIONS

用于检测细菌感染的阳离子类固醇化合物的合成

• 批准号: 9090097
• 负责人: Buck E. Rogers
• 金额: $ 22.81万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9090097
• 关键词: Abscess; Acids; Acute; Affinity; Amines; Anatomy; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Bacterial Proteins; Binding; Blood Vessels; Cause of Death; Chelating Agents; Chronic; Ciprofloxacin; Citrates; Clinical; Clinical Management; Communicable Diseases; Detection; Development; Discipline of Nuclear Medicine; Ensure; Eukaryotic Cell; Evaluation; Fever of Unknown Origin; Goals; Gram-Negative Bacteria; Health; Image; Immunocompromised Host; Implant; Infection; Inflammation; Kanamycin; Label; Leukocytes; Lung; Lung Inflammation; Membrane; Modeling; Monitor; Morphology; Mycoses; Osteomyelitis; Oximes; Oxyquinoline; Parents; Patients; Peptide Fragments; Peptides; Photons; Positron; Positron-Emission Tomography; Postoperative Period; Radioactive; Radioimmunoconjugate; Radiolabeled; Radiopharmaceuticals; Site; Specificity; Sterility; Steroids; Symptoms; Thymidine Kinase; Ultrasonography; Virus Diseases; X-Ray Computed Tomography; antimicrobial; antimicrobial drug; antimicrobial peptide; base; cancer imaging; chemokine; design; fluorodeoxyglucose; imaging agent; mortality; mouse model; novel; nucleoside analog; radiotracer; response; single photon emission computed tomography; triazacyclononane; uptake; whole body imaging

 DESCRIPTION (provided by applicant): Infectious diseases remain a major health problem and cause of death worldwide. The identification and localization of sites of infection in patients is a critical step in their clinical management, particularly when localized symptoms of the infection are not present. The prompt identification of infections can be cured with proper treatment, while delays can result in mortality. Anatomic imaging using ultrasound or computed tomography can be used for identification if local symptoms are present, however, they cannot differentiate between an infection and inflammation. Whole body scans in nuclear medicine imaging would be advantageous for imaging when there are no local symptoms of infection. There are a variety of radiopharmaceuticals that are used to detect infection and inflammation; however, it has been shown that the majority of these probes cannot distinguish between infection and inflammation. Therefore, the development of an imaging agent that is specific for detection of bacterial infections in a variety of clinical contexts would be highly significant. Soe progress has been made on the development of probes for the specific detection of viral, fungal, and bacterial infections. The use of radiolabeled antibiotics such as ciprofloxacin, kanamycin, and sulphanilamide for the detection of bacterial infections has been investigated, but there is concern about their specificity. The goal of this study is to develop a PET imaging agent based on a novel class of antimicrobial agents for the specific detection of bacterial infections. These novel antimicrobial agents are cationic steroid compounds, designed to mimic the morphology of endogenous antimicrobial peptides and have been shown to be effective against both Gram-positive and Gram-negative bacteria. These compounds display high and selective affinity for bacterial membranes over eukaryotic cells. In these studies, we will modify the cationic steroid antibiotics (CSAs) with the 1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA) chelator such that they can be radiolabeled with the positron-emitter, 64Cu. These conjugates will be evaluated to ensure that they maintain their activity against bacteria and then radiolabeled with 64Cu to determine uptake and affinity in bacterial cultures. The resulting radiolabeled conjugates will then be evaluated in a lung infection model in sterile inflammation to determine the specificity of the agent. The specific aims of the proposal are: 1.) Synthesize and evaluate CSAs that have been conjugated to NOTA and 2.) Evaluate 64Cu-NOTA-CSA conjugates in a lung infection model.

 描述（由申请人提供）：传染病仍然是全球主要的健康问题和死亡原因。患者感染部位的识别和定位 是其临床管理的关键步骤，特别是当不存在感染的局部症状时。及时发现感染可以通过适当治疗治愈，而延误则可能导致死亡。使用超声或计算机断层扫描的解剖成像可用于识别是否存在局部症状，但是，它们不能区分感染和炎症。当没有局部感染症状时，核医学成像中的全身扫描将有利于成像。有多种放射性药物可用于检测感染和炎症;然而，已表明大多数这些探针无法区分感染和炎症。因此，开发特异性用于检测各种临床环境中的细菌感染的成像剂将是非常重要的。用于病毒、真菌和细菌感染特异性检测的探针的开发已经取得了一些进展。放射性标记的抗生素如环丙沙星、卡那霉素和磺胺用于检测细菌感染已被研究过，但其特异性令人担忧。本研究的目的是开发一种基于新型抗菌剂的PET显像剂，用于细菌感染的特异性检测。这些新的抗微生物剂是阳离子类固醇化合物，旨在模拟内源性抗微生物肽的形态，并已被证明对革兰氏阳性和革兰氏阴性细菌都有效。这些化合物显示出对细菌膜的高选择性亲和力超过真核细胞。在这些研究中，我们将用1，4，7-三氮杂环壬烷-1，4，7-三乙酸（NOTA）螯合剂修饰阳离子类固醇抗生素（CSA），使得它们可以用正电子发射体64 Cu进行放射性标记。将对这些偶联物进行评价，以确保它们保持其抗细菌活性，然后用64 Cu进行放射性标记，以确定细菌培养物中的摄取和亲和力。然后在无菌炎症的肺部感染模型中评价所得放射性标记的缀合物，以确定试剂的特异性。该提案的具体目标是：1）。合成并评估已缀合至NOTA和2的CSA。在肺部感染模型中评估64 Cu-NOTA-CSA缀合物。

项目成果

Comparison of dosages, intervals, and drugs in the prevention of Pneumocystis carinii pneumonia.

预防卡氏肺孢子虫肺炎的剂量、间隔时间和药物比较。

• DOI: 10.1128/aac.32.5.623
• 发表时间: 1988
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Hughes,WT