Type IV Secretion System Therapeutics

描述（由申请人提供）：抗生素耐药性的日益流行正在损害我们治疗感染的能力。因此，该应用程序的广泛和长期目标是开发针对病原体宿主相互作用关键方面的新型治疗方法，这些治疗方法被预测为对抗微生物耐药性的敏感性要低得多。许多细菌病原体利用专门的分泌系统将毒力因子注入宿主细胞。这些系统对毒力是绝对必需的，因此提供了一个有希望的治疗靶点。本R21提案的目的是建立IV型分泌系统(T4SS) -此类注射器械的主要类别之一-作为抗菌治疗的靶点。实验拟：(1)利用高通量筛选方法在T4SS模型病原菌嗜肺军团菌中鉴定T4SS抑制剂；(2)通过对T4SS功能的多次二次分析，验证并表征了抑制活性的特异性；(3)基于几种公共卫生关注的病原体（包括美国疾病控制与预防中心优先考虑的病原体，如伯纳氏杆菌）的T4SS同源性，验证一些抑制剂将具有广泛活性的预测；(4)进行体内实验的原理验证。综上所述，这些实验应该为T4SS治疗及其作为新的人类治疗方法的潜在应用奠定理论基础。

DESCRIPTION (provided by applicant): The increasing prevalence of antibiotic resistance is compromising our ability to treat infection. Therefore, the application's broad, long-term objective is to develop novel therapeutics targeting critical aspects of pathogen host interaction that are predicted to be far less susceptible to anti-microbial resistance. 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 R21 proposal is to establish type IV secretion systems (T4SS) -- one of the major classes of such injection apparatuses - as a target for antimicrobial therapy. Experiments are proposed to: (1) identify T4SS inhibitors using a high throughput screening approach in the model T4SS pathogen, Legionella pneumophila; (2) validate and characterize the specificity of inhibitory activity through several secondary assays of T4SS function; (3) test the prediction that some inhibitors will be broadly active based on homology among T4SS from several agents of public health concern, including CDC priority agents such as Coxiella burnetii; and (4) perform proof of principle in vivo experiments. Taken together these experiments should establish the theoretical basis for T4SS therapy and their potential use as new human therapeutics. 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.