Host-Directed Strategies to Create Synergistic Antibacterial Therapies

 描述(申请人提供)：新出现的抗生素耐药性是一种全球健康危机。从广泛耐药的“超级细菌”到极端耐药的结核分枝杆菌(XDR-TB)，无法治愈的细菌感染的幽灵已经成为一个令人震惊的现实。这个问题变得如此严重，以至于巴拉克·奥巴马总统最近发布了一项行政命令，称多重耐药细菌是国家安全的优先事项。同样，需要开发更好的抗生素，缩短治愈持续性细菌感染的治疗时间，这也是一个主要目标，特别是对包括结核分枝杆菌在内的一些最臭名昭著的人类病原体来说。由于新抗生素从实验室涌现的速度很慢，通过修改现有药物或开发针对新细菌靶点的抑制剂来对抗抗生素耐药性和持久性不太可能跟上日益增长的需求。该项目的目标是采用一种完全不同的方法来开发新的抗生素，方法是确定 以天然免疫细胞强大的宿主免疫通路为靶点的小分子，创造出与传统抗生素协同作用的辅助疗法。这种方法与传统的抗生素开发计划是相反的，传统的抗生素开发计划寻求识别针对细菌基本途径但避免宿主途径的分子抑制剂。“宿主导向疗法”(HDTS)的潜在影响可能是巨大的，因为它们可能会使耐药菌株重新敏感，并缩短根除慢性感染的时间。特别是，这项提议试图将我们对宿主-病原体相互作用的理解转化为一种新的程序，用于识别针对宿主过程的小分子，这些小分子将在结核病感染期间与传统抗生素协同作用。成功的影响可能不仅仅是细菌感染，因为这种方法可能对广泛的感染性病原体产生巨大影响，甚至可以提高疫苗的效力。

 DESCRIPTION (provided by applicant): Emerging antibiotic resistance is a global health crisis. From broadly resistant "superbugs" to extremely drug resistant Mycobacterium tuberculosis (XDR-TB), the specter of untreatable bacterial infection has become an alarming reality. The problem has become so acute that President Barack Obama recently issued an executive order calling multidrug resistant bacteria a national security priority. Likewise, the need to develop better antibiotics that shorten the treatment time to cure persistent bacterial infections also remains a major goal, especially for some of the most notorious pathogens of man, including M. tuberculosis. Due to the slow rate of new antibiotics emerging from the lab, countering antibiotic resistance and persistence by modifying existing drugs or developing inhibitors to new bacterial targets is unlikely to keep up with the increasing demand. The goal of this project is to take a radically different approach to new antibiotic development by identifying small molecules that target powerful host immune pathways of innate immune cells, creating adjunctive therapies that will synergize with conventional antibiotics. This approach is antithetical to traditional antibiotic development programs, which seek to identify molecular inhibitors that target essential pathways of the bacterium but avoid host pathways. The potential impact of "Host-Directed Therapies" (HDTs) could be dramatic, as they may re-sensitize drug-resistant strains and shorten the time to eradicate chronic infections. In particular, this proposa seeks to translate our understanding of host-pathogen interactions into a novel program for identifying small molecules targeting host processes that will synergize with traditional antibiotics during TB infection. The implications of success may extend beyond bacterial infection, as this approach could have huge implications for a broad range of infectious agents, and even boost vaccine efficacy.