Type IV Secretion System Therapeutics

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，该申请的广泛的长期目标是开发针对病原体宿主相互作用的关键方面的新型治疗剂，这些方面预计对抗微生物耐药性的敏感性要低得多。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。这项R21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。实验建议：（1）在模型T4 SS病原体嗜肺军团菌中使用高通量筛选方法鉴定T4 SS抑制剂;（2）通过T4 SS功能的几种次级测定验证和表征抑制活性的特异性;（3）基于来自几种公共卫生关注物的T4 SS之间的同源性，测试一些抑制剂将具有广泛活性的预测，包括CDC优先药剂，如贝氏柯克斯体;和（4）进行体内实验的原理证明。总之，这些实验应该为T4 SS治疗及其作为新的人类疗法的潜在用途建立理论基础。 公共卫生相关性：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。

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.