Mycobacterial PDIM/PGL: synthesis pathway and inhibition

分枝杆菌 PDIM/PGL：合成途径和抑制

• 批准号: 7085210
• 负责人: LUIS E QUADRI
• 金额: $ 36.78万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085210
• 关键词: Mycobacterium; bacteria; biosynthesis; bioterrorism /chemical warfare; cell membrane; cell wall; chemotherapy; diol; glycolipids; infection; lipids; model; public health; role; tuberculosis; university; virulence

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mt), the etiologic agent of tuberculosis (TB), is a pathogen with a serious impact on global public health and a potential agent for bioterrorism. Mt spreads by airborne droplets and inhalation of 1-10 bacteria is sufficient to produce an infection that can result in symptomatic disease. The Center for Disease Control has included multiple-drug resistant (MDR) Mt in Category C of biological agents for public health preparedness against bioterrorism. MDR TB is considered an emerging infectious disease.. The mortality rate of untreatable MDR TB is 40-60%. The threat of MDR TB outbreaks resistant to all current anti-TB drugs, resulting either from natural emergence or bioterrorism, is an alarming scenario. Public health preparedness against MDR TB requires development of new chemotherapies against conventional and unconventional Mt targets to kill the bacterium or impair its virulence or growth in the host. Mt enzymes needed for synthesis of lipids and glycolipids required for virulence are targets for alternative drugs, which alone or in combination therapies, will be useful in prophylaxis and treatment of MDR TB. Such drugs will represent an important line of biodefense in the event of outbreaks of unstoppable Mt infections resistant to all conventional available antibiotics. Elucidation of the biosynthesis of these Mt lipids/glycolipids is an important step towards accelerating development of such drugs. Recent studies revealed that a group of cell-envelope-localized Mt lipids (referred to as PDIMs) is required for full virulence in animal infection models. Production of PDIM-related glycolipids (referred to as PGLs) was recently demonstrated to be responsible for Mt hypervirulent phenotype in a mouse model. Additional studies indicate that PGLs and PDIMs are involved in pathways that counteract host immune mechanisms. These facts suggest that PDIMs and PGLs (collectively referred to as DPKs) play an important role in TB pathogenesis. The proposed studies will investigated several hypothesized steps in DPK synthesis and explore the development of a first PGL synthesis inhibitor. The knowledge gained will provide important insight into DPK synthesis and reveal avenues for development of DPK synthesis inhibitors that will serve as valuable lead compounds in the development of novel anti-TB drugs and tools to decipher the relevance of DPK at specific stages of infection since they could be used to temporally control DPK synthesis in animal models.

描述（由申请人提供）：结核分枝杆菌（MT），结核病的病因（TB）是一种病原体，对全球公共卫生和潜在的生物恐怖主义具有严重影响。 MT通过机载液滴扩散，吸入1-10个细菌足以产生可能导致有症状疾病的感染。疾病控制中心包括在生物恐怖主义的公共卫生准备中，在生物健康的C类中包括多药耐药（MDR）MT。 MDR结核病被认为是一种新兴的传染病。不可治疗的MDR TB的死亡率为40-60％。 MDR TB暴发的威胁是由于自然出现或生物恐怖主义造成的所有当前抗TB药物的抗性，这是一个令人震惊的情况。针对MDR结核病的公共卫生准备需要开发针对常规和非常规MT靶标的新化学疗法，以杀死细菌或损害其在宿主中的毒力或增长。毒力所需的脂质和糖脂合成所需的MT酶是单独或联合疗法中的替代药物的靶标，可用于预防和治疗MDR TB。在发生不可阻挡的MT感染对所有常规可用抗生素的抗药性爆发时，此类药物将代表重要的生物陷入困境。阐明这些MT脂质/糖脂的生物合成是迈向加速此类药物发展的重要一步。最近的研究表明，在动物感染模型中完全毒力需要一组细胞 - 嵌入式MT脂质（称为PDIMS）。最近证明，与PDIM相关的糖脂（称为PGLS）的产生是在小鼠模型中负责MT高毒性表型的原因。其他研究表明，PGL和PDIMS参与抵消宿主免疫机制的途径。这些事实表明，PDIM和PGL（统称为DPK）在TB发病机理中起着重要作用。拟议的研究将研究DPK合成中的几个假设步骤，并探索第一个PGL合成抑制剂的发展。获得的知识将为DPK综合提供重要的见解，并揭示了DPK合成抑制剂发展的途径，这些途径将作为开发新型抗TB药物和工具的有价值的铅化合物，以破译DPK在特定感染阶段的相关性，因为它们可用于在动物模型中的时间内部控制DPK综合。