Novel Antimicrobials Targeting Bacterial Type IV Secretion Systems

针对 IV 型细菌分泌系统的新型抗菌药物

• 批准号: 9123514
• 负责人: JAMES E KIRBY
• 金额: $ 39.15万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123514
• 关键词: Antibiotic Resistance; Antibiotics; Area; Bacteria; Bacterial Typing; Bartonella; Bartonella Infections; Biological Assay; Blood; Cells; Communicable Diseases; Coxiella burnetii; Data; Disease; Elements; Exploratory/Developmental Grant; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Future; Goals; Growth; Human; Infection; Injection of therapeutic agent; Legionella pneumophila; Libraries; Maximum Tolerated Dose; Metabolic; Modeling; Mus; Organism; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Prevalence; Resistance; Series; Specificity; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Tissues; Toxic effect; Type IV Secretion System Pathway; Virulence; Virulence Factors; Work; analog; antimicrobial; antimicrobial drug; base; follow-up; high throughput screening; in vitro Assay; in vivo; in vivo Model; inhibitor/antagonist; macrophage; mouse model; novel; novel therapeutics; pathogen; research study; resistance mechanism; scaffold; screening; small molecule inhibitor; therapeutic target

DESCRIPTION (provided by applicant): The increasing prevalence of antibiotic resistance is compromising our ability to treat infection. Therefore, this application's broad, long-term objective is to develop and establish proof of principle for a new class of therapeutics targeting pathogen host interaction. Many bacterial pathogens use specialized secretion systems to inject virulence factors into host cells. These systems are absolutely required for virulence and therefore offer a promising therapeutic target. The aim of this proposal is to establish type IV secretion systems (T4SS) -- one of the major classes of such injection apparatuses - as a target for antimicrobial therapy. We recently completed a high throughput screen of a 235,000 compound library using the model pathogen, Legionella pneumophila, in order to identify small molecule inhibitors of T4SS. Here, we propose to follow up on preliminary data obtained from this screening effort with three specific aims. In the first, experiments are proposed to characterize previously identified, strong screening hits in order to confirm specificity, define potency, and characterize activity spectrum in L. pneumophila, Coxiella burnetii and a series of more distantly related T4SS-dependent pathogens. In the second, iterative structure-activity relationship studies will be used to identify analogues with the enhanced pharmacological potential. In the third, the activity of select small molecule inhibitors will be characterized in ivo in murine models of infection with L. pneumophila, C. burnetii, and Bartonella. Taken together these experiments should establish the theoretical basis for T4SS therapy and its potential use as a new human therapeutic.

描述（由申请人提供）：抗生素耐药性的增加正在损害我们治疗感染的能力。因此，该应用程序的广泛长期目标是为针对病原体宿主相互作用的新型治疗剂开发和建立原理证明。许多细菌病原体使用专门的分泌系统将毒力因子注入宿主细胞。这些系统绝对需要毒力，因此提供了有希望的治疗靶标。该提案的目的是建立IV型分泌系统（T4SS）（T4SS）（此类注射设备的主要类别之一）作为抗菌治疗的靶标。最近，我们使用模型病原体肺炎军团菌（Legionella Pneumophila）完成了235,000个化合物库的高吞吐量筛选，以鉴定T4SS的小分子抑制剂。在这里，我们建议跟进从此筛选工作中获得的初步数据，并以三个特定的目标进行。首先，提出了实验来表征先前鉴定的强烈筛选，以确认特异性，定义效力和表征肺炎乳杆菌，Coxiella burnetii和一系列更遥远的T4SS依赖性病原体中的活性谱。在第二个中，迭代结构 - 活性关系研究将用于识别具有增强药理潜力的类似物。在第三次中，将在IVO中表征精选的小分子抑制剂的活性在肺炎乳杆菌，伯内特氏菌和巴托氏菌感染的鼠模型中。综上所述，这些实验应建立T4SS治疗的理论基础及其作为新的人类治疗方法的潜在用途。