Mycobacterial PDIM/PGL: synthesis pathway and inhibition

描述（申请人提供）：结核分枝杆菌（Mt）是结核病（TB）的病原体，是一种严重影响全球公共卫生的病原体，也是生物恐怖主义的潜在病原体。结核分枝杆菌通过空气中的飞沫传播，吸入1-10个细菌就足以引起感染，并导致症状性疾病。美国疾病控制中心已将耐多药结核分枝杆菌列入C类生物制剂，用于公共卫生防范生物恐怖主义。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所有现有的抗结核药物都具有耐药性，这是一种令人担忧的情况，可能是自然出现的，也可能是生物恐怖主义造成的。针对耐多药结核病的公共卫生准备工作需要开发针对常规和非常规结核病目标的新化疗，以杀死细菌或削弱其在宿主中的毒力或生长。合成毒性所需的脂质和糖脂所需的MT酶是替代药物的靶点，其单独或联合治疗将用于预防和治疗MDR TB。这些药物将代表一个重要的生物防御线，在不可阻挡的Mt感染爆发的情况下，所有常规可用的抗生素耐药。阐明这些Mt脂质/糖脂的生物合成是加速此类药物开发的重要一步。最近的研究表明，在动物感染模型中，一组细胞包膜定位的Mt脂质（称为PDIM）是完全毒力所必需的。PDIM相关糖脂（称为PGLs）的产生最近被证明是Mt在小鼠模型中的高毒力表型的原因。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PGL（统称为DPKs）在TB发病机制中起重要作用。本研究将探讨DPK合成中的几个假设步骤，并探索第一个PGL合成抑制剂的开发。所获得的知识将提供重要的洞察DPK合成，并揭示DPK合成抑制剂的开发途径，这些抑制剂将在开发新型抗TB药物和工具中用作有价值的先导化合物，以破译DPK在感染的特定阶段的相关性，因为它们可以用于暂时控制动物模型中的DPK合成。

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.