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（由应用程序提供）：传染病仍然是全球的主要健康问题和死亡原因。患者感染部位的鉴定和定位 是他们临床管理的关键一步，尤其是在不存在感染的局部症状时。可以通过适当的治疗方法来迅速识别感染，而延迟可能导致死亡率。如果存在局部症状，则使用超声或计算机断层扫描的解剖成像可用于识别，但是，它们无法区分感染和炎症。当没有局部感染症状时，核医学成像中的全身扫描对于成像是有利的。有多种用于检测感染和感染的放射性药物。但是，已经表明，这些问题中的大多数无法区分感染和感染。因此，在多种临床环境中检测细菌感染的特定成像剂的发展将非常重要。 SOE的进步已经在发展病毒，真菌和细菌感染的特定问题的发展方面取得了进展。已经研究了使用放射性标记的抗生素，例如环丙沙星，卡纳米霉素和磺胺酰胺来检测细菌感染，但人们担心它们的特异性。这项研究的目的是基于一类新型抗菌剂的宠物成像剂，以特异性检测细菌感染。这些新型的抗菌剂是阳离子类固醇化合物，旨在模仿内源性抗菌胡椒的形态，并已被证明是有效的，以抗革兰氏阳性和革兰氏阴性细菌。这些化合物表现出对细菌膜上真核细胞的高和选择性亲和力。在这些研究中，我们将用1、4、7-三氮唑烷烷-1、4、7-烹饪乙酸（Nota）螯合剂来修饰阳离子类固醇抗生素（CSA），以使它们可以用阳性emitter进行放射性标记，64cu。将评估这些结合物，以确保它们对细菌保持活性，然后用64CU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，将在无菌炎症的肺部感染模型中评估所得的放射性标记的缀合物，以确定药物的特异性。该提案的具体目的是：1。）合成和评估已与Nota结合的CSA和2。）评估肺部感染模型中的64CU-NOTA-CSA结合物。

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