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: 8439168
• 负责人: JAMES E KIRBY
• 金额: $ 39万
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439168
• 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; Relative (related person); Resistance; Screening procedure; 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; novel; novel therapeutics; pathogen; research study; resistance mechanism; scaffold; small molecule; 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. PUBLIC HEALTH RELEVANCE: The proposal will identify and characterize new therapeutic agents that target a critical interaction between pathogen and host. We predict these new drugs will be less susceptible to resistance mechanisms that compromise efficacy of traditional antibiotics, and therefore will provide a powerful new therapy for infectious diseases.

描述（由申请人提供）：抗生素耐药性的日益普遍正在损害我们治疗感染的能力。因此，本申请的广泛、长期目标是开发和建立靶向病原体宿主相互作用的一类新疗法的原理证明。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。这些系统是绝对需要的毒力，因此提供了一个有前途的治疗目标。该提案的目的是建立IV型分泌系统（T4 SS）-这类注射装置的主要类别之一-作为抗菌治疗的目标。我们最近完成了一个高通量筛选的235,000化合物库使用的模式病原体，嗜肺军团菌，以确定T4 SS的小分子抑制剂。在这里，我们建议对从这一筛选工作中获得的初步数据进行跟踪，具体目标有三个。首先，提出实验来表征先前鉴定的强筛选命中，以确认特异性，定义效价，并表征L中的活性谱。嗜肺热菌、贝氏柯克斯体（Coxiella burnetii）和一系列关系更远的T4 SS依赖性病原体。在第二，迭代的结构-活性关系的研究将被用来确定类似物与增强的药理潜力。在第三项研究中，将在感染乳杆菌的小鼠模型中，对所选小分子抑制剂的活性进行体内表征。pneumophila、嗜肺假丝酵母C.伯内特氏菌和巴尔通体。总之，这些实验应该为T4 SS疗法及其作为新的人类治疗剂的潜在用途奠定理论基础。 公共卫生关系：该提案将确定和表征针对病原体和宿主之间关键相互作用的新治疗剂。我们预测，这些新药将不太容易受到传统抗生素疗效受损的耐药机制的影响，因此将为感染性疾病提供强大的新疗法。