Mycobacterial PDIM/PGL: synthesis pathway and inhibition

结核分枝杆菌（Mycobacterium tuberculosis，Mt）是结核病（TB）的病原体， 对全球公共卫生的影响和生物恐怖主义的潜在因素。结核分枝杆菌通过空气飞沫传播， 吸入1- 10个细菌就足以产生感染，从而导致症状性疾病。的 美国疾病控制中心已将多药耐药（MDR）结核分枝杆菌列入C类生物制剂 公共卫生准备应对生物恐怖主义。耐多药结核病被认为是一种新兴的传染病。 无法治疗的耐多药结核病的死亡率为40- 60%。耐多药结核病爆发的威胁对目前所有的耐药结核病都具有抗药性 自然产生或生物恐怖主义导致的抗结核药物的短缺是一个令人担忧的情况。公共卫生 对耐多药结核病的准备需要开发新的化学疗法， 非常规MT的目标是杀死细菌或削弱其毒力或在宿主中的生长。Mt酶 合成毒性所需的脂质和糖脂所需的药物是替代药物的靶点， 单独或联合治疗，将有助于缓解和治疗MDR TB。这些药物将 代表了一条重要的生物防御线，以防爆发无法阻止的结核分枝杆菌感染， 所有常规可用的抗生素。这些Mt脂质/糖脂的生物合成的阐明是一个新的研究方向。 这是加快开发此类药物的重要步骤。最近的研究表明， 细胞包膜定位的MT脂质（称为PDIM）是动物感染中完全毒力所必需的 模型PDIM相关糖脂（称为PGLs）的产生最近被证明是 在小鼠模型中负责Mt高毒力表型。其他研究表明，PGLs和 PDIM参与抵消宿主免疫机制的途径。这些事实表明，PDIM 和PGLs（统称为DPKs）在TB发病机制中起重要作用。拟议 研究将调查DPK合成中的几个假设步骤，并探索第一个 PGL合成抑制剂。所获得的知识将提供重要的洞察DPK合成和揭示 开发DPK合成抑制剂的途径，这些抑制剂将作为有价值的先导化合物， 开发新型抗结核药物和工具，以破译DPK在感染特定阶段的相关性 因为它们可用于暂时控制动物模型中的DPK合成。

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 1-10bacteria 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 prophylaxisand 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.