Host-Directed Strategies to Create Synergistic Antibacterial Therapies

创建协同抗菌疗法的宿主导向策略

• 批准号: 9143637
• 负责人: JEFFERY S COX
• 金额: $ 78.5万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9143637
• 关键词: Acute; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Cells; Chronic; Development; Drug resistance; Drug resistance in tuberculosis; Extreme drug resistant tuberculosis; Goals; Health; Immune; Infection; Infectious Agent; Molecular; Multi-Drug Resistance; Mycobacterium tuberculosis; National Security; Pathway interactions; Pharmaceutical Preparations; Process; Program Development; Resistance; Superbug; Time; Translating; global health; inhibitor/antagonist; man; novel; pathogen; programs; resistant strain; small molecule; success; vaccine efficacy

 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.

 描述（由适用提供）：新兴的抗生素耐药性是全球健康危机。从广泛的“超级细菌”到极端耐药性分枝杆菌（XDR-TB），不可治疗的细菌感染的幽灵已成为令人震惊的现实。这个问题变得如此严重，以至于巴拉克·奥巴马（Barack Obama）最近发布了一项行政命令，称耐多药细菌为国家安全优先事项。同样，开发更好的抗生素的需求缩短治疗时间以治愈持续细菌感染的时间也是一个主要目标，尤其是对于包括结核分枝杆菌的某些最臭名昭著的人病原体。由于从实验室出现的新抗生素速率缓慢，因此通过修改现有药物或将抑制剂培养为新细菌靶标的抗生素耐药性和持久性不太可能跟上需求不断增长的需求。该项目的目的是通过识别出一种根本不同的方法来进行新的抗生素开发 针对先天免疫细胞的强大宿主免疫途径的小分子，产生辅助疗法，可与常规抗生素协同作用。这种方法与传统的抗生素发展计划相反，该程序试图鉴定针对细菌基本途径但避免宿主途径的分子抑制剂。 “宿主指导疗法”（HDTS）的潜在影响可能是戏剧性的，因为它们可能会重新抗药性菌株并缩短放射性慢性感染的时间。特别是，该提案旨在将我们对宿主 - 病原体相互作用的理解转化为一个新的程序，用于识别针对宿主过程的小分子，该程序将在结核病感染过程中与传统抗生素协同作用。成功的含义可能会超越细菌感染，因为这种方法可能对广泛的传染药具有巨大影响，甚至可以提高疫苗效率。